doi: 10.1161/01.CIR.0000120390.68287.BB
(Circulation. 2004;109:1580-1589.)
© 2004 American Heart Association, Inc.
Review: Current Perspective |
Hypertrophy of the Heart
A New Therapeutic Target?
From the Department of Cardiology (Innere Medizin III), University of Heidelberg (N.F., H.A.K.), Heidelberg, Germany, and Departments of Molecular Biology (E.N.O., J.A.H.) and Internal Medicine (J.A.H.) and the Donald W. Reynolds Cardiovascular Clinical Research Center (E.N.O., J.A.H.), University of Texas Southwestern Medical Center, Dallas, Tex.
Correspondence to Joseph A. Hill, MD, PhD, Cardiology Division, Department of Internal Medicine, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-8573. E-mail joseph.hill{at}UTsouthwestern.edu
 |
Abstract |
|---|
 Top Abstract IntroductionCa2+/Calcineurin/Nuclear Factor...G-Protein-Coupled ReceptorsPhosphoinositide 3...Myocyte Enhancer Factor...Peroxisome Proliferator...Small G ProteinsBiomechanical Sensors in...Na/H ExchangerCa2+ CyclingPhysiological Versus...Evidence From Clinical TrialsCaveatsSummaryReferences |
|---|
Recent studies call into question the necessity of hypertrophic growth of the heart as a "compensatory" response to hemodynamic stress. These findings, coupled with recent progress in dissecting the molecular bases of hypertrophy, raise the prospect of suppressing hypertrophy without provoking circulatory insufficiency. In this article, we focus on signaling pathways that hold promise as potential targets for therapeutic intervention. We also summarize observations from animal models and clinical trials that suggest benefit from an antihypertrophic strategy.
Key Words: hypertrophy • heart failure • signal transduction
|
Introduction |
|---|
|
TopAbstractIntroductionCa2+/Calcineurin/Nuclear Factor...G-Protein-Coupled ReceptorsPhosphoinositide 3...Myocyte Enhancer Factor...Peroxisome Proliferator...Small G ProteinsBiomechanical Sensors in...Na/H ExchangerCa2+ CyclingPhysiological Versus...Evidence From Clinical TrialsCaveatsSummaryReferences |
|---|
Cardiac hypertrophy is an adaptive response to pressure or volume stress, mutations of sarcomeric (or other) proteins, or loss of contractile mass from prior infarction. Hypertrophic growth accompanies many forms of heart disease, including ischemic disease, hypertension, heart failure, and valvular disease. In these types of cardiac pathology, pressure overload-induced concentric hypertrophy is believed to have a compensatory function by diminishing wall stress and oxygen consumption.1–3 At the same time, ventricular hypertrophy is associated with significantly increased risk of heart failure and malignant arrhythmia.4,5
In the 1960s, Meerson and colleagues6 divided hypertrophic transformation of the heart into 3 stages: (1) developing hypertrophy, in which load exceeds output, (2) compensatory hypertrophy, in which the workload/mass ratio is normalized and resting cardiac output is maintained, and (3) overt heart failure, with ventricular dilation and progressive declines in cardiac output despite continuous activation of the hypertrophic program. The late-phase "remodeling" process that leads to failure is associated with functional perturbations of cellular Ca2+ homeostasis7 and ionic currents, 8,9 which contribute to an adverse prognosis by predisposing to ventricular dysfunction and malignant arrhythmia. Significant morphological changes include increased rates of apoptosis,10 fibrosis, and chamber dilation. Even though the dichotomy between adaptive and maladaptive hypertrophy has been appreciated for more than a century,11 mechanisms that determine how long-standing hypertrophy ultimately progresses to overt heart failure are poorly understood.
At the cellular level, cardiomyocyte hypertrophy is characterized by an increase in cell size, enhanced protein synthesis, and heightened organization of the sarcomere. Classically, 2 different hypertrophic phenotypes can be distinguished: (1) concentric hypertrophy due to pressure overload, which is characterized by parallel addition of sarcomeres and lateral growth of individual cardiomyocytes, and (2) eccentric hypertrophy due to volume overload or prior infarction, characterized by addition of sarcomeres in series and longitudinal cell growth.12 At the molecular level, these changes in cellular phenotype are accompanied by reinduction of the so-called fetal gene program, because patterns of gene expression mimic those seen during embryonic development.
Hypertrophy that occurs as a consequence of pressure overload is termed "compensatory" on the premise that it facilitates ejection performance by normalizing systolic wall stress. Recent experimental results, however, call into question the necessity of normalization of wall stress that results from hypertrophic growth of the heart. These findings, largely from studies in genetically engineered mice, raise the prospect of modulating hypertrophic growth of the myocardium to afford clinical benefit without provoking hemodynamic compromise.
To accomplish this goal, it is essential to identify molecular events involved in the hypertrophic process, a topic reviewed recently,13,14 and to identify commonalities and differences in the signaling systems that promote pathological hypertrophy versus physiological hypertrophy.15 Especially critical is elucidation of mechanisms underlying the maladaptive features of hypertrophy, such as arrhythmogenicity and transformation to heart failure. Here, we summarize recent observations from animal models and clinical trials that identify signaling cascades that hold promise as potential targets for therapeutic intervention. We focus on pathways that have been investigated as antihypertrophic targets and omit several important pathways, such as mitogen-activated protein kinase (reviewed in Sugden and Clerk16) or the Gp130/Stat3 (reviewed in Hoshijima and Chien17), in which interruption has not been studied carefully as a potential therapeutic strategy.
|
Ca2+/Calcineurin/Nuclear Factor of Activated T Cells |
|---|
|
TopAbstractIntroductionCa2+/Calcineurin/Nuclear Factor...G-Protein-Coupled ReceptorsPhosphoinositide 3...Myocyte Enhancer Factor...Peroxisome Proliferator...Small G ProteinsBiomechanical Sensors in...Na/H ExchangerCa2+ CyclingPhysiological Versus...Evidence From Clinical TrialsCaveatsSummaryReferences |
|---|
Calcineurin is a protein phosphatase that dephosphorylates transcription factors of the NFAT (nuclear factor of activated T cells) family, which leads to their translocation to the nucleus to activate target genes. It is well established that activation of the calcineurin/NFAT pathway is sufficient for the development of cardiac hypertrophy and failure.18 However, establishing whether calcineurin is necessary for this process has been more problematic. Controversy regarding this issue derives from conflicting results in studies in vivo using the calcineurin inhibitors cyclosporine A (CsA) and FK506 to treat various models of hypertrophy. Many studies have reported attenuation of hypertrophy by CsA and FK506 (reviewed in Frey and Olson13 and Leinwand19). However, there have also been studies that reported no significant attenuation of hypertrophy in vivo. In humans, immunosuppressive therapy after solid-organ transplantation is associated with cardiac hypertrophy secondary to drug-induced hypertension and nephrotoxicity20,21; that CsA treatment does not suppress hypertrophic growth is not surprising given that much higher doses of CsA (or FK506) are required to suppress calcineurin activity in the heart relative to T cells.22 In animal studies, differences in experimental methodology, including differences in timing and dosing of drug treatment, and differences in species and strain likely contribute to these apparent discrepancies. However, as outlined below, this controversy has been resolved by the use of more specific, endogenous calcineurin inhibitors.
These early hypertrophy-prevention studies provided an opportunity to test the long-held tenet that cardiac hypertrophy is a required compensatory response to hemodynamic stress. For the first time, hypertrophic growth could be abolished while the inciting stimulus, pressure stress, was maintained. Surprisingly, in animals in which hypertrophy was eliminated by calcineurin suppression, no evidence of hemodynamic compromise was observed, at least over a period of several weeks.23 Despite persistent increases in wall stress as predicted by Laplace’s law, ventricular size and systolic function (as suggested by a normal ejection fraction) were preserved, and the animals were clinically healthy with normal longevity (Table). Although it is presently unclear whether this lack of adverse effect would be sustained over long periods of time in larger mammals, these findings suggest that calcineurin-mediated hypertrophic growth may not be a required compensatory response, at least under conditions of moderate stress. In so doing, they raise the prospect that therapies could be developed to modulate the hypertrophic response to mitigate maladaptive aspects of the phenotype.
|
More recent studies have relied on endogenous inhibition of calcineurin by genetic means. Overexpression in cardiomyocytes of AKAP79 or Cain/Cabin, molecules that associate with the calcineurin catalytic subunit and inhibit activity, blunts both phenylephrine- and angiotensin II-induced hypertrophy.24 These results were extended in vivo, where transgenic overexpression of Cain/Cabin resulted in attenuation of both pressure-overload and isoproterenol-induced cardiac hypertrophy.25 Forced expression of a dominant-negative calcineurin mutant confers protection against hypertrophy and fibrosis after abdominal aortic constriction,26 and targeted ablation of the calcineurin-Aß gene blunts the hypertrophic response to hormonal or pressure stress.27
In contrast to AKAP70 and Cain/Cabin, members of a family of calcineurin-interacting proteins termed DSCR1/MCIPs (modulatory calcineurin-interacting protein) are expressed at high levels in striated muscle and may function as endogenous modulators of calcineurin in the heart.28–30 Cardiac overexpression of MCIP1 inhibited the progression to dilated cardiomyopathy in MCIP1/calcineurin double-transgenic mice.31 Moreover, hypertrophic growth induced by isoproterenol, exercise, or thoracic aortic banding were all blunted in this model.31,32 Recent data from mice with targeted deletion of MCIP1 suggest a dual role for MCIP1 in the regulation of calcineurin activity, viz low levels of MCIP1 expression may facilitate calcineurin signaling, but eventually MCIP1 must dissociate from calcineurin for full activation.33
Given that calcineurin-dependent signaling is involved in many, if not all, causes of cardiac hypertrophy, it is an attractive target for the prevention and treatment of hypertrophic heart disease. Mice that overexpress MCIP1 and are subjected to surgical pressure overload are clinically healthy despite significant blunting of the hypertrophic growth response.32 Noninvasive and hemodynamic measures of cardiac performance are normal as late as 3 months, the latest time point examined. These findings confirm that cardiomyocyte-autonomous suppression of cardiac hypertrophy does not provoke hemodynamic collapse. However, it remains to be seen whether these data can be confirmed in studies with longer observation periods or in large animals. Moreover, the finding that exercise-induced cardiac hypertrophy is attenuated in MCIP1-transgenic hearts suggests that calcineurin plays a role in "physiological" hypertrophy as well. It is conceivable that a baseline level of calcineurin activity is required to prevent atrophy of the heart. For example, calcineurin-mediated NFAT activation is critical in preventing cardiomyocyte apoptosis.34 Thus, a major challenge for the future will be to tailor calcineurin inhibition spatially and quantitatively to prevent the injurious sequelae of overactive calcineurin without provoking adverse effects on the physiological function of the heart (and other tissues).
|
G-Protein-Coupled Receptors |
|---|
|
TopAbstractIntroductionCa2+/Calcineurin/Nuclear Factor...G-Protein-Coupled ReceptorsPhosphoinositide 3...Myocyte Enhancer Factor...Peroxisome Proliferator...Small G ProteinsBiomechanical Sensors in...Na/H ExchangerCa2+ CyclingPhysiological Versus...Evidence From Clinical TrialsCaveatsSummaryReferences |
|---|
Myocardial G-protein-coupled receptors (GPCRs), including adrenergic, angiotensin, and endothelin (ET-1) receptors, serve a fundamental role in the regulation of cardiac function and hypertrophic growth,35,36 and they are the site of action of numerous clinically useful drugs. GPCRs are coupled to 3 principal classes of heterotrimeric GTP-binding proteins, G
s, Gq/G11, and Gi, which transduce agonist-induced signals to intracellular effectors such as enzymes and ion channels.
Activation of Gq-coupled receptors is sufficient to induce hypertrophy in vitro and cardiomyopathy in vivo (reviewed in Adams et al37 and Koch et al38). Combined genetic ablation of the Gq and G11 genes results in embryonic lethality due to myocardial hypoplasia.39 Cardiac-specific ablation of G11/Gq in adult animals results in an almost complete lack of cardiac hypertrophy in response to aortic banding,40 and overexpression of a dominant-negative mutant of Gq in transgenic mouse hearts blunts pressure-overload hypertrophy.41 Noteworthy is the fact that transgenic animals display a significantly slower pace of deterioration of systolic function than wild-type controls despite a documented lack of normalization of wall stress.42 Similar findings were reported in mice lacking dopamine ß-hydroxylase, the essential enzyme for the synthesis of norepinephrine.42 Together, these findings lend further support to the hypothesis that cardiac hypertrophy is neither required nor necessarily adaptive, at least not in rodent models for up to 3 months (Table).
Cardiac overexpression of ß1-receptors, the most abundant adrenergic receptor in the heart, or Gs, its downstream effector, initially increases contractile function but eventually results in cardiomyocyte hypertrophy, fibrosis, and progressive deterioration of cardiac performance.43–45 Interestingly, overexpression of ß2-receptors, which couple to both Gs and Gi,46 is detrimental only at excessive levels (>100-fold), whereas moderate levels of expression improve basal contractile function and rescue the cardiomyopathic phenotype of Gq-transgenic mice.47 Inhibition of ß-adrenergic receptor kinase (ßARK), a kinase involved in receptor desensitization, by overexpression of the inhibitory peptide ßARKct attenuates cardiomyopathy secondary to deficiency of the sarcomeric protein MLP.48 Moreover, ßARKct overexpression significantly blunts the development of cardiac hypertrophy and delays development of systolic dysfunction in calsequestrin transgenic mice, which again demonstrates the beneficial effects of inhibition of cardiac hypertrophy.49
|
Phosphoinositide 3-Kinase/Akt/Glycogen Synthase Kinase-3 |
|---|
|
TopAbstractIntroductionCa2+/Calcineurin/Nuclear Factor...G-Protein-Coupled ReceptorsPhosphoinositide 3...Myocyte Enhancer Factor...Peroxisome Proliferator...Small G ProteinsBiomechanical Sensors in...Na/H ExchangerCa2+ CyclingPhysiological Versus...Evidence From Clinical TrialsCaveatsSummaryReferences |
|---|
Phosphoinositide 3-kinases (PI3Ks) have been implicated in the regulation of many cellular functions, including cell growth, survival, and proliferation.50 Overexpression of a constitutively active PI3K (p110
) mutant in the heart leads to increased heart size; conversely, hearts expressing a dominant-negative PI3K are small.51 Interestingly, cardiac function under resting conditions was not perturbed in either model but declined in dominant-negative PI3K mice subjected to pressure overload but not in exercise-trained animals.52 One study demonstrated that pathways for hypertrophic growth and contractile function can be dissociated in vivo: p110-dependent signaling mediates cardiomyocyte hypertrophy, whereas p110
negatively regulates contractile function by inhibiting cAMP production without affecting cardiomyocyte size.53 An important target of PI3K signaling is the serine/threonine kinase Akt (also known as protein kinase B). Overexpression of Akt is sufficient to induce cardiac hypertrophy in transgenic mice without adverse effects on systolic function.54,55 Akt regulates at least 2 downstream targets in hypertrophic signaling, the mammalian target of rapamycin (mTor) and glycogen synthase kinase (GSK)-3. mTor activates key regulators of protein translation such as p70S6 kinase and 4EBP1/eIF4E, thereby enhancing protein synthesis, a classic feature of cardiomyocyte hypertrophy. Binding of the immunosuppressive drug rapamycin coupled to its intracellular receptor FKBP12 inhibits the activity of mTor. Rapamycin, a compound used successfully to treat transplant rejection in clinical practice, is able to attenuate cardiac hypertrophy secondary to constitutive activation of Akt56 or a variety of hypertrophic stimuli.57–60
Akt phosphorylates and thereby inhibits GSK-3ß, a widely expressed kinase that phosphorylates transcription factors of the NFAT family, promoting translocation to the cytoplasm, where they are inactive. The ß-adrenergic agonist isoproterenol61 and both endothelin-1 (ET-1) and phenylephrine62 induce GSK-3ß phosphorylation in a PI3K-dependent fashion, which indicates that inactivation of GSK-3ß might be required for hypertrophic growth. In fact, expression of a phosphorylation-resistant mutant of GSK-3ß results in inhibition of ET-1-mediated hypertrophy in vitro.62 Similarly, transgenic overexpression of this GSK-3ß mutant in mouse hearts significantly decreases hypertrophy in response to chronic isoproterenol administration and pressure overload.63 Of note, several other transcription factors implicated in the hypertrophic response are phosphorylated by GSK-3ß, including GATA4.64
Activation of GSK-3ß results in enhanced expression of atrial natriuretic peptide (ANP), while at the same time suppressing other genes in the "hypertrophic program."61,63 Activation of ANP-dependent signaling or its downstream mediators (guanylyl cyclase-A receptor, protein kinase G) evokes potent antihypertrophic effects in vitro and in vivo.65–68 It is tempting to speculate that the ability of GSK-3 to uncouple ANP expression from the fetal gene program contributes to its hypertrophy-suppressing properties.
Taken together, these findings support the notion that GSK-3 integrates signals of multiple hypertrophic pathways and that GSK-3 inactivation is required for the development of many forms of cardiac hypertrophy. Given this, GSK-3 is an attractive target for therapeutic intervention. However, the pleiotropic actions of GSK-3 in multiple tissues pose significant challenges, and a great deal more work is required.
|
Myocyte Enhancer Factor-2/Histone Deacetylases |
|---|
|
TopAbstractIntroductionCa2+/Calcineurin/Nuclear Factor...G-Protein-Coupled ReceptorsPhosphoinositide 3...Myocyte Enhancer Factor...Peroxisome Proliferator...Small G ProteinsBiomechanical Sensors in...Na/H ExchangerCa2+ CyclingPhysiological Versus...Evidence From Clinical TrialsCaveatsSummaryReferences |
|---|
Because several hypertrophic pathways are capable of evoking similar morphological and molecular phenotypes, it is plausible that these signaling cascades converge on common downstream targets. A candidate in this regard is MEF2 (myocyte enhancer factor-2). MEF2 proteins display only basal levels of transcriptional activity and become active only on upstream stimulation, thus fulfilling criteria for a potential integrator of "pathological" growth signals. Accordingly, transgenic expression of a dominant-negative mutant of MEF2 in mouse hearts results in impaired cardiac growth.69
MEF2 activity is regulated by direct association with histone acetylases (HATs) and deacetylases (HDACs; reviewed in McKinsey et al70). These chromatin remodeling enzymes are recruited to target genes by binding to specific transcription factors such as MEF2. HATs acetylate nucleosomal histones, promoting chromatin relaxation and transcriptional activation, and HDACs antagonize this function. Phosphorylation of class II HDACs by CaMK and other kinases disrupts their tight association with MEF2, which results in derepression of transcriptional activity and nuclear export of HDAC molecules. Accordingly, HDACs have been shown to inhibit hypertrophic signaling, serving as a "brake" on the myocardial growth response71 (Data Supplement Figure).
Mutant class II HDACs that lack regulatory phosphorylation sites render cardiomyocytes resistant to serum- or phenylephrine-induced hypertrophy and fetal gene activation. Mice that lack HDAC9 exhibit normal cardiac size and function at an early age but manifest an exaggerated response to thoracic aortic banding and calcineurin activation, which is accompanied by superinduction of "hypertrophic genes."71 Conversely, very recent results suggest that expression of antihypertrophic genes in the heart is inhibited by HDAC2, a class I HDAC.72 Thus, HDAC-mediated chromatin remodeling may regulate a relative balance between prohypertrophic and antihypertrophic transcriptional processes, opening new possibilities in the prevention and treatment of cardiac hypertrophy and failure. In general, regulation of transcriptional activity by chromatin structure and function is likely to emerge as a novel target for therapy.
|
Peroxisome Proliferator-Activated Receptors |
|---|
|
TopAbstractIntroductionCa2+/Calcineurin/Nuclear Factor...G-Protein-Coupled ReceptorsPhosphoinositide 3...Myocyte Enhancer Factor...Peroxisome Proliferator...Small G ProteinsBiomechanical Sensors in...Na/H ExchangerCa2+ CyclingPhysiological Versus...Evidence From Clinical TrialsCaveatsSummaryReferences |
|---|
Energy metabolism in the adult myocardium depends largely on mitochondrial oxidation of long-chain fatty acids. Cardiac hypertrophy is associated with suppression of fatty acid oxidation and metabolic reversion to increased glucose utilization, which is characteristic of the fetal heart (reviewed in Lehman and Kelly73). This shift could be viewed as an adaptive response, because it decreases oxygen consumption per mole of ATP generated. However, maladaptive features exist, including increased lipid accumulation in the heart stemming from chronically impaired oxidation of fatty acids,74 lactic acid accumulation, and diminished maximal ATP generation from glycolysis.
Genes involved in fatty acid oxidation are regulated by the peroxisome proliferator-activated receptor (PPAR) family of transcription factors. The 3 PPAR isoforms, , ß/
, and , belong to a superfamily of nuclear hormone receptors and are activated by diverse ligands, including unsaturated fatty acids and isoform-specific drugs such as fibrates (PPAR) and antidiabetic drugs of the thiazolidinedione class (PPAR). These latter agents attenuate angiotensin II-induced hypertrophic gene expression, as well as increases in cardiomyocyte size in vitro.75,76 Heterozygous PPAR-deficient mice display an exaggerated hypertrophic response to aortic banding, whereas the PPAR agonist pioglitazone significantly blunts myocardial hypertrophy in banded wild-type mice.75
PPAR, the predominant PPAR isoform in the heart, has been implicated in hypertrophic signaling. PPAR expression is significantly diminished during pressure-overload hypertrophy, along with several other key enzymes of lipid metabolism.77 Some evidence suggests that PPAR downregulation is an adaptive response: agonist-induced PPAR activation leads to contractile dysfunction in rat hearts subjected to pressure overload,78 and cardiac overexpression of PPAR leads to cardiomyopathy with contractile dysfunction.79 Genetically engineered mice lacking the PPAR gene were protected from diabetes-induced cardiac hypertrophy and dysfunction.80 Intriguingly, a single-nucleotide polymorphism within intron 7 of the PPAR gene independently predicted the degree of ventricular hypertrophy due to exercise in healthy volunteers.81 The significance of cardiac energy metabolism in the development and progression of myocardial hypertrophy is further highlighted by the recent finding that MEF2 and HDAC5 regulate the expression of PGC-1 (PPAR coactivator-1), a master regulator of mitochondrial biogenesis and fatty acid oxidation.82
|
Small G Proteins |
|---|
|
TopAbstractIntroductionCa2+/Calcineurin/Nuclear Factor...G-Protein-Coupled ReceptorsPhosphoinositide 3...Myocyte Enhancer Factor...Peroxisome Proliferator...Small G ProteinsBiomechanical Sensors in...Na/H ExchangerCa2+ CyclingPhysiological Versus...Evidence From Clinical TrialsCaveatsSummaryReferences |
|---|
Small G proteins play an important role in sarcomeric and cytoskeletal organization, hallmark features of the hypertrophic phenotype. Small G proteins also regulate such diverse processes as cell growth, division and survival, membrane trafficking, and cellular motility (reviewed in Clerk and Sugden83). Several small GTPases have been implicated in hypertrophy and studied as therapeutic targets.
Ras, the first small G protein shown to be involved in cardiac hypertrophy, induces a significant increase in cardiac mass when a constitutively active mutant is overexpressed in transgenic mouse hearts.84 Likewise, expression of this Ras mutant in neonatal rat cardiomyocytes results in hypertrophic gene expression,85 whereas dominant-negative Ras mutants blunt phenylephrine-mediated increases in cell size and protein synthesis.86,87
The Rho family of small G proteins, consisting of RhoA, Rac, and Cdc42 subfamilies, regulates cytoskeletal organization in cardiomyocytes.88 RhoA activates several protein kinases, specifically Rho-associated kinase (ROCK), and potentiates GATA4 transcriptional activity to induce a hypertrophic phenotype in neonatal rat cardiomyocytes.89 Dominant-negative RhoA mutants, as well as inhibitors of ROCK, prevent cardiomyocyte hypertrophy in vitro.90 However, overexpression of RhoA in transgenic mouse hearts is not sufficient to induce ventricular hypertrophy but rather leads to cardiac conduction abnormalities with bradycardia and ultimately a dilated phenotype and heart failure.91
Constitutive activation of Rac in cardiomyocytes in vitro92 and in vivo93 leads to hypertrophy associated with alterations in focal adhesions, whereas a dominant-negative Rac mutant prevents phenylephrine-induced increases in protein synthesis and cardiomyocyte size. Likewise, a dominant-negative focal adhesion kinase (FAK) attenuates the hypertrophic phenotype, as well as the induction of ANP expression, after either ET-194 or phenylephrine95 stimulation.
Signal transduction by small G proteins requires covalent attachment of isoprenoid intermediates (isoprenylation), which in turn leads to membrane targeting. Cholesterol-lowering drugs of the statin class (HMG-CoA reductase inhibitors) block formation of isoprenoid intermediates, thereby inhibiting small G protein function. Accordingly, both angiotensin II-induced96 and phenylephrine-induced97 cardiomyocyte hypertrophy are prevented by statin treatment in vitro. Simvastatin significantly reduces hypertrophy in rats with pressure overload due to aortic banding.98 Likewise, the hypertrophic and cardiomyopathic phenotype of a double-transgenic rat with overexpression of both renin and angiotensinogen is improved by cerivastatin treatment.99 Fluvastatin increases survival in a murine model of myocardial infarction.100 This effect is associated with attenuation of left ventricular dilation and lower end-diastolic pressures, which suggests a favorable effect on postinfarction ventricular remodeling. Patel et al101 demonstrated regression of myocardial hypertrophy and fibrosis in transgenic rabbits overexpressing a ß-MHC mutation after treatment with simvastatin. In fact, simvastatin inhibits cardiac hypertrophy due to aortic banding while simultaneously preventing Rho-geranylgeranylation.102 Statins inhibit hypertrophy in spontaneously hypertensive rats, accompanied by a decrease in the GTP-binding activity of Rac1 and RhoA.103 Although it is clear that prevention of acute vascular events underlies most of the substantial clinical benefit afforded by these drugs, it is tempting to speculate that suppression of myocyte small G-protein signaling plays some role.
|
Biomechanical Sensors in Hypertrophic Signaling |
|---|
|
TopAbstractIntroductionCa2+/Calcineurin/Nuclear Factor...G-Protein-Coupled ReceptorsPhosphoinositide 3...Myocyte Enhancer Factor...Peroxisome Proliferator...Small G ProteinsBiomechanical Sensors in...Na/H ExchangerCa2+ CyclingPhysiological Versus...Evidence From Clinical TrialsCaveatsSummaryReferences |
|---|
Mechanical stress induced by physical stretching of neonatal or adult cardiomyocytes is sufficient to induce hypertrophic gene expression and a hypertrophic phenotype, notably in the absence of humoral or neuronal factors (reviewed in Sadoshima and Izumo104), which suggests a cell-autonomous mechanism. Mechanical stress induces a number of growth responses, including activation of several hypertrophic signaling cascades, increases in protein synthesis, and release of vasoactive peptides (reviewed in Zou et al105). As noted earlier, different types of biomechanical stimuli, such as pressure or volume, induce distinct molecular responses. Despite the pathophysiological importance of biomechanical stress-induced growth responses, and their potential candidacy for therapy, little is known about how biomechanical stress is sensed by the cardiomyocyte and transduced into prohypertrophic intracellular signals.
Several potential mediators of "mechanosensing" have been proposed, including stretch-activated ion channels and integrins. Mice lacking melusin, a protein that interacts with ß1-integrin at the costamere, fail to mount a significant hypertrophic response to pressure stress but rather display a dilated phenotype with severely depressed cardiac function.106 In contrast, administration of subpressor doses of angiotensin II or phenylephrine in these mice leads to cardiac hypertrophy indistinguishable from wild-type mice, which suggests a specific role for melusin in the transmission of biomechanical stress. Other data suggest that mechanotransduction may occur at the sarcomeric Z disk. Cardiomyocytes derived from mice lacking the Z-disc protein MLP (muscle LIM protein) selectively fail to respond to stretch, whereas the response to Gq-coupled agonists is not compromised.107 Moreover, a human mutation within the MLP gene that disrupts telethonin/T-cap binding leads to dilated cardiomyopathy.107 We recently identified a new family of striated muscle-specific Z-disc proteins, termed calsarcins, which interact with both telethonin/T-cap and calcineurin,108 which suggests a possible role in linking mechanosensation to hypertrophic signaling.
|
Na/H Exchanger |
|---|
|
TopAbstractIntroductionCa2+/Calcineurin/Nuclear Factor...G-Protein-Coupled ReceptorsPhosphoinositide 3...Myocyte Enhancer Factor...Peroxisome Proliferator...Small G ProteinsBiomechanical Sensors in...Na/H ExchangerCa2+ CyclingPhysiological Versus...Evidence From Clinical TrialsCaveatsSummaryReferences |
|---|
Cardiac Na+/H+-exchanger (NHE) activity is upregulated in several in vivo and in vitro models of cardiac hypertrophy.109,110 Elevated NHE activity depletes the transmembrane Na+ gradient, which leads to increased intracellular Ca2+ mediated by the Na/Ca-exchanger (reviewed in Cingolani and de Hurtado111) and consequent activation of several signaling cascades (reviewed in Frey and Olson13). Accordingly, inhibition of NHE by its specific inhibitor cariporide has been demonstrated to "rescue" several models of cardiac hypertrophy in vivo.111–113 Because NHE inhibition does not appear to be associated with adverse hemodynamic consequences, this approach is a potentially interesting antihypertrophic treatment option.
|
Ca2+ Cycling |
|---|
|
TopAbstractIntroductionCa2+/Calcineurin/Nuclear Factor...G-Protein-Coupled ReceptorsPhosphoinositide 3...Myocyte Enhancer Factor...Peroxisome Proliferator...Small G ProteinsBiomechanical Sensors in...Na/H ExchangerCa2+ CyclingPhysiological Versus...Evidence From Clinical TrialsCaveatsSummaryReferences |
|---|
Considerable attention has been focused on abnormalities of Ca2+ cycling in hypertrophy as a possible therapeutic target. In heart failure, diminished systolic Ca2+ transients derive, at least in part, from depletion of Ca2+ stores. This depletion, in turn, stems from the synergistic actions of (1) adrenergic activation, (2) decreased expression of the sarcoplasmic reticulum Ca2+ pump SERCA2a, and (3) hypophosphorylation of phospholamban, which augments the tonic inhibitory action of phospholamban on SERCA2a. Exciting therapeutic approaches have been directed at restoring sarcoplasmic reticulum Ca2+ stores, either by decreasing ß-adrenergic receptor activity,114 overexpressing SERCA2a115,116 or the Ca2+-binding protein S100A1,117 or eliminating phospholamban.118,119 Indeed, the cardiomyopathic phenotype in several120–123 but not all124 genetic models can be rescued by targeted deletion of phospholamban. Recent reports, however, have described missense125 or nonsense126 mutations in phospholamban in familial pedigrees of dilated cardiomyopathy, which highlights the challenges that lie ahead in envisioning Ca2+ cycling as a therapeutic target.
|
Physiological Versus Pathological Hypertrophy |
|---|
|
TopAbstractIntroductionCa2+/Calcineurin/Nuclear Factor...G-Protein-Coupled ReceptorsPhosphoinositide 3...Myocyte Enhancer Factor...Peroxisome Proliferator...Small G ProteinsBiomechanical Sensors in...Na/H ExchangerCa2+ CyclingPhysiological Versus...Evidence From Clinical TrialsCaveatsSummaryReferences |
|---|
In some instances, such as in endurance athletes, cardiac hypertrophy is generally accepted to be physiological and not associated with adverse sequelae. Little is known, however, about the specific molecular events that lead to physiological hypertrophy and how these pathways differ from pathological hypertrophy. The morphological phenotypes differ significantly: Exercise-induced hypertrophy is typically not accompanied by myocardial accumulation of collagen, and increases in wall thickness are modest. Scheuer and coworkers127 demonstrated that physiological and pathological hypertrophy differ in their respective myosin isoform compositions and that the predominance of myosin V3 expression in hypertensive rats could be reversed by chronic exercise. Spontaneously hypertensive rats express higher levels of "hypertrophic genes," such as brain natriuretic peptide or ET-1, compared with exercised rats, despite similar degrees of left ventricular hypertrophy.128 Transcriptional profiling of exercised rat hearts demonstrated downregulation of hypertrophic "markers."129 Similarly, both thyroid hormone receptor expression and
/ß-MHC isoform expression are regulated in opposite directions in exercise-induced hypertrophy compared with that induced by pressure overload.130 Pressure and volume stress induce distinct molecular responses; despite a similar degree of hypertrophy and ANP induction, marked differences in the expression levels of ß-myosin, -skeletal actin, and SERCA2a were observed in pressure overload-induced hypertrophy relative to volume overload.131 Taken together, hypertrophic signaling can be viewed as a web that integrates and modulates a multitude of input signals (Figure). Whereas multiple endogenous and exogenous inhibitors of cardiac hypertrophy have been identified, it will be critical to specifically target "pathological" hypertrophy while preserving the heart’s ability to adapt to an increase in physiological demands. Some evidence suggests this may be possible.
|
|
Evidence From Clinical Trials |
|---|
|
TopAbstractIntroductionCa2+/Calcineurin/Nuclear Factor...G-Protein-Coupled ReceptorsPhosphoinositide 3...Myocyte Enhancer Factor...Peroxisome Proliferator...Small G ProteinsBiomechanical Sensors in...Na/H ExchangerCa2+ CyclingPhysiological Versus...Evidence From Clinical TrialsCaveatsSummaryReferences |
|---|
Most modern treatments of heart failure, including ß-blockers and ACE inhibitors, aim to delay or even reverse the maladaptive remodeling process, and there is a great deal of evidence to support their use in patients with structural heart disease. It is difficult, however, to derive mechanistic insights from many clinical studies, because the beneficial impact of energy-sparing therapies (eg, afterload reduction, heart rate lowering) is confounding. Recent trials comparing treatments with similar blood pressure-lowering effects suggest that interruption of hypertrophic signaling pathways may confer differing degrees of clinical benefit. In the Losartan Intervention For Endpoint reduction in hypertension (LIFE) trial, 9139 patients with hypertension and ECG-documented left ventricular hypertrophy were randomized to receive either the AT1 receptor blocker losartan or the ß1-receptor blocker atenolol. Whereas the blood pressure-lowering effects were similar, patients taking losartan displayed significantly less hypertrophy and were less likely (relative risk 0.87, P=0.02) to suffer a major cardiovascular event.132 In the Heart Outcomes Prevention Evaluation (HOPE) trial, the ACE inhibitor ramipril afforded significant clinical benefit133 and decreased the development (and caused regression) of hypertrophy134 independently of its blood pressure-lowering effects. In contrast, persistence of cardiac hypertrophy (despite similar blood pressure changes) predicted an adverse outcome. Together, these findings are consistent with results from animal models, which suggests that angiotensin (G
q/11) signaling may induce a maladaptive form of hypertrophy that can be suppressed to provide clinical benefit. The recent Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) has generated considerable debate, but its findings have been used to argue against -adrenergic blockade as a primary mean of blood pressure lowering.135,136 |
Caveats |
|---|
|
TopAbstractIntroductionCa2+/Calcineurin/Nuclear Factor...G-Protein-Coupled ReceptorsPhosphoinositide 3...Myocyte Enhancer Factor...Peroxisome Proliferator...Small G ProteinsBiomechanical Sensors in...Na/H ExchangerCa2+ CyclingPhysiological Versus...Evidence From Clinical TrialsCaveatsSummaryReferences |
|---|
Detailed dissection of hypertrophic signaling raises the prospect of enhancing the desirable features of hypertrophy (eg, increased sarcomere organization) while inhibiting maladaptive features (eg, decompensation, arrhythmogenesis, and contractile isoform switching). Several caveats pertain. Reports demonstrating benefit from inhibition of cardiac hypertrophy despite persistence of the initiating stimulus have been short term (
10% to 15% of a normal mouse lifespan); long-term targeting of hypertrophy in a heart with increased wall stress might still result in failure. In addition, certain hypertrophic signaling pathways may need to be basally active to prevent myocyte atrophy. Thus, strategies for suppressing excessive activation of such pathways may need to be titrated precisely to avoid disruption of cardiac homeostatic mechanisms. Finally, studies to date have focused on caged rodents with short life spans, and work using large animal models is required. |
Summary |
|---|
|
TopAbstractIntroductionCa2+/Calcineurin/Nuclear Factor...G-Protein-Coupled ReceptorsPhosphoinositide 3...Myocyte Enhancer Factor...Peroxisome Proliferator...Small G ProteinsBiomechanical Sensors in...Na/H ExchangerCa2+ CyclingPhysiological Versus...Evidence From Clinical TrialsCaveatsSummaryReferences |
|---|
Taken together, these data suggest that hypertrophy may be a valid, independent target for therapeutic intervention in selected patients. However, it remains to be seen whether hypertrophy induced by diverse forms of stress responds similarly to interruption of these pathways. Moreover, because of the pleiotropic actions of drugs used in some of these studies, it is unclear whether novel therapies that selectively target mediators of hypertrophic signaling also confer clinical benefits.
Recent discoveries demonstrating that the "compensatory" role of cardiac hypertrophy is not universally required may have uncovered a chink in the armor of hypertrophy. Major challenges remain to dissect mechanisms underlying the maladaptive features of hypertrophy, but patients with heart disease are likely to benefit from these efforts.
|
Acknowledgments |
|---|
This work was supported by grants from the Donald W. Reynolds Cardiovascular Clinical Research Center at UT Southwestern (Drs Olson and Hill) and Bundesministerium für Bildung und Forschung HK-S13T02 (Dr Frey). We gratefully acknowledge the thoughtful advice and careful reading of the manuscript provided by Dr Beverly Rothermel. We thank Scott Stone and Eric Cordell for graphics design and programming support with the interactive Data Supplement Figure.
|
Footnotes |
|---|
The interactive Data Supplement Figure is provided with the online-only version of this article at http://www.circulationaha.org.
|
References |
|---|
|
TopAbstractIntroductionCa2+/Calcineurin/Nuclear Factor...G-Protein-Coupled ReceptorsPhosphoinositide 3...Myocyte Enhancer Factor...Peroxisome Proliferator...Small G ProteinsBiomechanical Sensors in...Na/H ExchangerCa2+ CyclingPhysiological Versus...Evidence From Clinical TrialsCaveatsSummaryReferences |
|---|
1. Sandler H, Dodge HT. Left ventricular tension and stress in man. Circ Res. 1963; 13: 91–104.
2. Hood WP, Rackley CE, Rolett EL. Wall stress in the normal and hypertrophied human left ventricle. Am J Cardiol. 1968; 22: 550–558.[CrossRef][Medline] [Order article via Infotrieve]
3. Grossman W, Jones D, McLaurin LP. Wall stress and patterns of hypertrophy in the human left ventricle. J Clin Invest. 1975; 56: 56–64.[Medline] [Order article via Infotrieve]
4. Levy D, Garrison RJ, Savage DD, et al. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med. 1990; 322: 1561–1566.[Abstract]
5. Koren MJ, Devereux RB, Casale PN, et al. Relation of left ventricular mass and geometry to morbidity and mortality in uncomplicated essential hypertension. Ann Int Med. 1991; 114: 345–352.
6. Meerson FZ. On the mechanism of compensatory hyperfunction and insufficiency of the heart. Cor Vasa. 1961; 3: 161–177.[Medline] [Order article via Infotrieve]
7. Bers DM. Cardiac excitation-contraction coupling. Nature. 2002; 415: 198–205.[CrossRef][Medline] [Order article via Infotrieve]
8. Armoundas AA, Wu R, Juang G, et al. Electrical and structural remodeling of the failing ventricle. Pharmacol Ther. 2001; 92: 213–230.[CrossRef][Medline] [Order article via Infotrieve]
9. Hill JA. Electrical remodeling in cardiac hypertrophy. Trends Cardiovasc Med. 2003; 13: 316–322.[CrossRef][Medline] [Order article via Infotrieve]
10. Haunstetter A, Izumo S. Toward antiapoptosis as a new treatment modality. Circ Res. 2000; 86: 371–376.
11. Osler W. The Principles and Practice of Medicine. New York: D. Appleton and Co; 1892.
12. Dorn GW II, Robbins J, Sugden PH. Phenotyping hypertrophy: eschew obfuscation. Circ Res. 2003; 92: 1171–1175.
13. Frey N, Olson EN. Cardiac hypertrophy: the good, the bad and the ugly. Annu Rev Physiol. 2003; 65: 45–79.[CrossRef][Medline] [Order article via Infotrieve]
14. Akazawa H, Komuro I. Roles of cardiac transcription factors in cardiac hypertrophy. Circ Res. 2003; 92: 1079–1088.
15. Katz AM. Cardiomyopathy of overload: a major determinant of prognosis in congestive heart failure. N Engl J Med. 1990; 322: 100–110.[Medline] [Order article via Infotrieve]
16. Sugden PH, Clerk A. Cellular mechanisms of cardiac hypertrophy. J Mol Med. 1998; 76: 725–746.[CrossRef][Medline] [Order article via Infotrieve]
17. Hoshijima M, Chien KR. Mixed signals in heart failure: cancer rules. J Clin Invest. 2002; 109: 849–855.[CrossRef][Medline] [Order article via Infotrieve]
18. Molkentin JD, Lu J-R, Antos CL, et al. A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell. 1998; 93: 215–228.[CrossRef][Medline] [Order article via Infotrieve]
19. Leinwand LA. Calcineurin inhibition and cardiac hypertrophy: a matter of balance. Proc Natl Acad Sci U S A. 2001; 98: 2947–2949.
20. Ventura HO, Malik FS, Mehra MR, et al. Mechanisms of hypertension in cardiac transplantation and the role of cyclosporine. Curr Opin Cardiol. 1997; 12: 375–381.[Medline] [Order article via Infotrieve]
21. Imakita M, Tazelaar HD, Rowan RA, et al. Myocyte hypertrophy in the transplanted heart: a morphometric analysis. Transplantation. 1987; 43: 839–842.[Medline] [Order article via Infotrieve]
22. Olson EN, Williams RS. Calcineurin signaling and muscle remodeling. Cell. 2000; 101: 689–692.[CrossRef][Medline] [Order article via Infotrieve]
23. Hill JA, Karimi M, Kutschke W, et al. Cardiac hypertrophy is not a required compensatory response to short-term pressure overload. Circulation. 2000; 101: 2863–2869.
24. Taigen T, De Windt LJ, Lim HW, et al. Targeted inhibition of calcineurin prevents agonist-induced cardiomyocyte hypertrophy. Proc Natl Acad Sci U S A. 2000; 97: 1196–1201.
25. De Windt LJ, Lim HW, Bueno OF, et al. Targeted inhibition of calcineurin attenuates cardiac hypertrophy in vivo. Proc Natl Acad Sci U S A. 2001; 98: 3322–3327.
26. Zou Y, Hiroi Y, Uozumi H, et al. Calcineurin plays a critical role in the development of pressure overload-induced cardiac hypertrophy. Circulation. 2001; 104: 97–101.
27. Bueno OF, Wilkins BJ, Tymitz KM, et al. Impaired cardiac hypertrophic response in calcineurin Abeta-deficient mice. Proc Natl Acad Sci U S A. 2002; 99: 4586–4591.
28. Rothermel BA, Vega RB, Yang J, et al. A protein encoded within the Down syndrome critical region is enriched in striated muscles and inhibits calcineurin signaling. J Biol Chem. 2000; 275: 8719–8725.
29. Kingsbury TJ, Cunningham KW. A conserved family of calcineurin regulators. Genes Dev. 2000; 14: 1595–1604.
30. Yang J, Rothermel BA, Vega RB, et al. Independent signals control expression of the calcineurin inhibitory proteins MCIP1 and MCIP2 in striated muscles. Circ Res. 2001; 87: e61–e68.
31. Rothermel BA, McKinsey TA, Vega RB, et al. Myocyte-enriched calcineurin-interacting protein, MCIP1, inhibits cardiac hypertrophy in vivo. Proc Natl Acad Sci U S A. 2001; 98: 3328–3333.
32. Hill JA, Rothermel BA, Yoo K-D, et al. Targeted inhibition of calcineurin in pressure-overload hypertrophy: preservation of systolic function. J Biol Chem. 2002; 277: 10251–10255.
33. Vega RB, Rothermel BA, Weinheimer CJ, et al. Dual roles of modulatory calcineurin-interacting protein 1 in cardiac hypertrophy. Proc Natl Acad Sci U S A. 2003; 100: 669–674.
34. Pu WT, Ma Q, Izumo S. NFAT transcription factors are critical survival factors that inhibit cardiomyocyte apoptosis during phenylephrine stimulation in vitro. Circ Res. 2003; 92: 725–731.
35. Rockman HA, Koch WJ, Lefkowitz RJ. Seven-transmembrane-spanning receptors and heart function. Nature. 2002; 415: 206–212.[CrossRef][Medline] [Order article via Infotrieve]
36. Esposito G, Rapacciuolo A, Naga Prasad SV, et al. Cardiac hypertrophy: role of G protein-coupled receptors. J Card Fail. 2002; 8: S409–S414.[CrossRef][Medline] [Order article via Infotrieve]
37. Adams JW, Sakata Y, Davis MG, et al. Enhanced G alpha q signaling: a common pathway mediates cardiac hypertrophy and apoptotic heart failure. Proc Natl Acad Sci U S A. 1998; 95: 10140–10145.
38. Koch WJ, Lefkowitz RJ, Rockman HA. Functional consequences of altering myocardial adrenergic receptor signaling. Annu Rev Physiol. 2000; 62: 237–260.[CrossRef][Medline] [Order article via Infotrieve]
39. Offermanns S, Zhao LP, Gohla A, et al. Embryonic cardiomyocyte hypoplasia and craniofacial defects in G alpha(q)/G alpha(11)-mutant mice. EMBO J. 1998; 17: 4304–4312.[CrossRef][Medline] [Order article via Infotrieve]
40. Wettschureck N, Rutten H, Zywietz A, et al. Absence of pressure overload induced myocardial hypertrophy after conditional inactivation of G alpha(q)/G alpha(11) in cardiomyocytes. Nat Med. 2001; 7: 1236–1240.[CrossRef][Medline] [Order article via Infotrieve]
41. Akhter SA, Luttrell LM, Rockman HA, et al. Targeting the receptor-Gq interface to inhibit in vivo pressure overload myocardial hypertrophy. Science. 1998; 280: 574–577.
42. Esposito G, Rapacciuolo A, Naga Prasad SV, et al. Genetic alterations that inhibit in vivo pressure-overload hypertrophy prevent cardiac dysfunction despite increased wall stress. Circulation. 2002; 105: 85–92.
43. Bisognano JD, Weinberger HD, Bohlmeyer TJ, et al. Myocardial-directed overexpression of the human beta(1)-adrenergic receptor in transgenic mice. J Mol Cell Cardiol. 2000; 32: 817–830.[CrossRef][Medline] [Order article via Infotrieve]
44. Gaudin C, Ishikawa Y, Wight DC, et al. Overexpression of G(S-alpha) protein in the hearts of transgenic mice. J Clin Invest. 1995; 95: 1676–1683.[Medline] [Order article via Infotrieve]
45. Engelhardt S, Hein L, Wiesmann F, et al. Progressive hypertrophy and heart failure in beta(1)-adrenergic receptor transgenic mice. Proc Natl Acad Sci U S A. 1999; 96: 7059–7064.
46. Daaka Y, Luttrell LM, Lefkowitz RJ. Switching of the coupling of the beta(2)-adrenergic receptor to different G proteins by protein kinase A. Nature. 1997; 390: 88–91.[CrossRef][Medline] [Order article via Infotrieve]
47. Dorn GW, Tepe NM, Lorenz JN, et al. Low- and high-level transgenic expression of beta(2)-adrenergic receptors differentially affect cardiac hypertrophy and function in G alpha q-overexpressing mice. Proc Natl Acad Sci U S A. 1999; 96: 6400–6405.
48. Rockman HA, Chien KR, Choi DJ, et al. Expression of a beta-adrenergic receptor kinase 1 inhibitor prevents the development of myocardial failure in gene-targeted mice. Proc Natl Acad Sci U S A. 1998; 95: 7000–7005.
49. Harding VB, Jones LR, Lefkowitz RJ, et al. Cardiac beta ARK1 inhibition prolongs survival and augments beta blocker therapy in a mouse model of severe heart failure. Proc Natl Acad Sci U S A. 2001; 98: 5809–5814.
50. Cantley LC. The phosphoinositide 3-kinase pathway. Science. 2002; 296: 1655–1657.
51. Shioi T, Kang PM, Douglas PS, et al. The conserved phosphoinositide 3-kinase pathway determines heart size in mice. EMBO J. 2000; 19: 2537–2548.[CrossRef][Medline] [Order article via Infotrieve]
52. McMullen JR, Shioi T, Zhang L, et al. Phosphoinositide 3-kinase(p110 alpha) plays a critical role for the induction of physiological, but not pathological, cardiac hypertrophy. Proc Natl Acad Sci U S A. 2003; 100: 12355–12360.
53. Crackower MA, Oudit GY, Kozieradzki I, et al. Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways. Cell. 2002; 110: 737–749.[CrossRef][Medline] [Order article via Infotrieve]
54. Matsui T, Li L, Wu JC, et al. Phenotypic spectrum caused by transgenic overexpression of activated Akt in the heart. J Biol Chem. 2002; 277: 22896–22901.
55. Condorelli G, Drusco A, Stassi G, et al. Akt induces enhanced myocardial contractility and cell size in vivo in transgenic mice. Proc Natl Acad Sci U S A. 2002; 99: 12333–12338.
56. Shioi T, McMullen JR, Kang PM, et al. Akt/protein kinase B promotes organ growth in transgenic mice. Mol Cell Biol. 2002; 22: 2799–2809.
57. Tu VC, Bahl JJ, Chen QM. Signals of oxidant-induced cardiomyocyte hypertrophy: key activation of p70 S6 kinase-1 and phosphoinositide 3-kinase. J Pharmacol Exp Ther. 2002; 300: 1101–1110.
58. Boluyt MO, Zheng JS, Younes A, et al. Rapamycin inhibits alpha(1)-adrenergic receptor-stimulated cardiac myocyte hypertrophy but not activation of hypertrophy-associated genes: evidence for involvement of p70 S6 kinase. Circ Res. 1997; 81: 176–186.
59. Sadoshima J, Izumo S. Rapamycin selectively inhibits angiotensin-II-induced increase in protein-synthesis in cardiac myocytes in vitro: potential role of 70-kD S6 kinase in angiotensin-II-induced cardiac hypertrophy. Circ Res. 1995; 77: 1040–1052.
60. Shioi T, McMullen JR, Tarnavski O, et al. Rapamycin attenuates load-induced cardiac hypertrophy in mice. Circulation. 2003; 107: 1664–1670.
61. Morisco C, Zebrowski D, Condorelli G, et al. The Akt-glycogen synthase kinase 3 beta pathway regulates transcription of atrial natriuretic factor induced by beta-adrenergic receptor stimulation in cardiac myocytes. J Biol Chem. 2000; 275: 14466–14475.
62. Haq S, Choukroun G, Kang ZB, et al. Glycogen synthase kinase-3 beta is a negative regulator of cardiomyocyte hypertrophy. J Cell Biol. 2000; 151: 117–129.
63. Antos CL, McKinsey TA, Frey N, et al. Activated glycogen synthase-3ß suppresses cardiac hypertrophy in vivo. Proc Natl Acad Sci U S A. 2002; 99: 907–909.
64. Morisco C, Seta K, Hardt SE, et al. Glycogen synthase kinase 3 beta regulates GATA4 in cardiac myocytes. J Biol Chem. 2001; 276: 28586–28597.
65. Kuhn M, Holtwick R, Baba HA, et al. Progressive cardiac hypertrophy and dysfunction in atrial natriuretic peptide receptor (GC-A) deficient mice. Heart. 2002; 87: 368–374.
66. Kishimoto I, Rossi K, Garbers DL. A genetic model provides evidence that the receptor for atrial natriuretic peptide (guanylyl cyclase-A) inhibits cardiac ventricular myocyte hypertrophy. Proc Natl Acad Sci U S A. 2001; 98: 2703–2706.
67. Holtwick R, van Eickels M, Skryabin BV, et al. Pressure-independent cardiac hypertrophy in mice with cardiomyocyte-restricted inactivation of the atrial natriuretic peptide receptor guanylyl cyclase-A. J Clin Invest. 2003; 111: 1399–1407.[CrossRef][Medline] [Order article via Infotrieve]
68. Fiedler B, Lohmann SM, Smolenski A, et al. Inhibition of calcineurin-NFAT hypertrophy signaling by cGMP-dependent protein kinase type I in cardiac myocytes. Proc Natl Acad Sci U S A. 2002; 99: 11363–11368.
69. Kolodziejczyk SM, Wang L, Balazsi K, et al. MEF2 is upregulated during cardiac hypertrophy and is required for normal post-natal growth of the myocardium. Curr Biol. 1999; 9: 1203–1206.[CrossRef][Medline] [Order article via Infotrieve]
70. McKinsey TA, Zhang CL, Olson EN. MEF2: a calcium-dependent regulator of cell division, differentiation and death. Trends Biochem Sci. 2002; 27: 40–47.[CrossRef][Medline] [Order article via Infotrieve]
71. Zhang CL, McKinsey TA, Chang S, et al. Class II histone deacetylases act as signal-responsive repressors of cardiac hypertrophy. Cell. 2002; 110: 479–488.[CrossRef][Medline] [Order article via Infotrieve]
72. Kook H, Lepore JJ, Gitler AD, et al. Cardiac hypertrophy and histone deacetylase-dependent transcriptional repression mediated by the atypical homeodomain protein Hop. J Clin Invest. 2003; 112: 863–871.[CrossRef][Medline] [Order article via Infotrieve]
73. Lehman JJ, Kelly DP. Gene regulatory mechanisms governing energy metabolism during cardiac hypertrophic growth. Heart Fail Rev. 2002; 7: 175–185.[CrossRef][Medline] [Order article via Infotrieve]
74. Barger PM, Kelly DP. PPAR signaling in the control of cardiac energy metabolism. Trends Cardiovasc Med. 2000; 10: 238–245.[CrossRef][Medline] [Order article via Infotrieve]
75. Asakawa M, Takano H, Nagai T, et al. Peroxisome proliferator-activated receptor gamma plays a critical role in inhibition of cardiac hypertrophy in vitro and in vivo. Circulation. 2002; 105: 1240–1246.
76. Yamamoto K, Ohki R, Lee RT, et al. Peroxisome proliferator-activated receptor gamma activators inhibit cardiac hypertrophy in cardiac myocytes. Circulation. 2001; 104: 1670–1675.
77. Lehman JJ, Barger PM, Kovacs A, et al. Peroxisome proliferator-activated receptor gamma coactivator-1 promotes cardiac mitochondrial biogenesis. J Clin Invest. 2000; 106: 847–856.[Medline] [Order article via Infotrieve]
78. Young ME, Laws FA, Goodwin GW, et al. Reactivation of peroxisome proliferator-activated receptor alpha is associated with contractile dysfunction in hypertrophied rat heart. J Biol Chem. 2001; 276: 44390–44395.
79. Finck BN, Lehman JJ, Leone TC, et al. The cardiac phenotype induced by PPAR alpha overexpression mimics that caused by diabetes mellitus. J Clin Invest. 2002; 109: 121–130.[CrossRef][Medline] [Order article via Infotrieve]
80. Finck BN, Han XL, Courtois M, et al. A critical role for PPAR alpha-mediated lipotoxicity in the pathogenesis of diabetic cardiomyopathy: modulation by dietary fat content. Proc Natl Acad Sci U S A. 2003; 100: 1226–1231.
81. Jamshidi Y, Montgomery HE, Hense HW, et al. Peroxisome proliferator-activated receptor a gene regulates left ventricular growth in response to exercise and hypertension. Circulation. 2002; 105: 950–955.
82. Czubryt MP, McAnally J, Fishman GI, et al. Regulation of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha) and mitochondrial function by MEF2 and HDAC5. Proc Natl Acad Sci U S A. 2003; 100: 1711–1716.
83. Clerk A, Sugden PH. Small guanine nucleotide-binding proteins and myocardial hypertrophy. Circ Res. 2000; 86: 1019–1023.
84. Hunter JJ, Tanaka N, Rockman HA, et al. Ventricular expression of a MLC-2v-ras fusion gene induces cardiac hypertrophy and selective diastolic dysfunction in transgenic mice. J Biol Chem. 1995; 270: 23173–23178.
85. Fuller SJ, Gillespie-Brown J, Sugden PH. Oncogenic src, raf, and ras stimulate a hypertrophic pattern of gene expression and increase cell size in neonatal rat ventricular myocytes. J Biol Chem. 1998; 273: 18146–18152.
86. Thornburn A. Ras activity is required for phenylephrine-induced activation of mitogen-activated protein kinase in cardiac muscle cells. Biochem Biophys Res Commun. 1994; 205: 1417–1422.[CrossRef][Medline] [Order article via Infotrieve]
87. Abdellatif M, Packer SE, Michael LH, et al. A Ras-dependent pathway regulates RNA polymerase II phosphorylation in cardiac myocytes: implications for cardiac hypertrophy. Mol Cell Biol. 1998; 18: 6729–6736.
88. Hoshijima M, Sah VP, Wang YB, et al. The low molecular weight GTPase rho regulates myofibril formation and organization in neonatal rat ventricular myocytes: involvement of Rho kinase. J Biol Chem. 1998; 273: 7725–7730.
89. Charron F, Tsimiklis G, Areand M, et al. Tissue-specific GATA factors are transcriptional effectors of the small GTPase RhoA. Genes Dev. 2001; 15: 2702–2719.
90. Sah VP, Hoshijima M, Chien KR, et al. Rho is required for G alpha(q) and alpha(1)-adrenergic receptor signaling in cardiomyocytes: dissociation of Ras and Rho pathways. J Biol Chem. 1996; 271: 31185–31190.
91. Sah VP, Minamisawa S, Tam SP, et al. Cardiac-specific overexpression of RhoA results in sinus and atrioventricular nodal dysfunction and contractile failure. J Clin Invest. 1999; 103: 1627–1634.[Medline] [Order article via Infotrieve]
92. Eble DM, Strait JB, Govindarajan G, et al. Endothelin-induced cardiac myocyte hypertrophy: role for focal adhesion kinase. Am J Physiol Heart Circ Physiol. 2000; 278: H1695–H1707.
93. Sussman MA, Welch S, Walker A, et al. Altered focal adhesion regulation correlates with cardiomyopathy in mice expressing constitutively active rac1. J Clin Invest. 2000; 105: 875–886.[Medline] [Order article via Infotrieve]
94. Eble DM, Strait JB, Govindarajan G, et al. Endothelin-induced cardiac myocyte hypertrophy: role for focal adhesion kinase. Am J Physiol Heart Circ Physiol. 2000; 278: H1695–H1707.
95. Taylor JM, Rovin JD, Parsons JT. A role for focal adhesion kinase in phenylephrine-induced hypertrophy of rat ventricular cardiomyocytes. J Biol Chem. 2000; 275: 19250–19257.
96. Oi S, Haneda T, Osaki J, et al. Lovastatin prevents angiotensin II-induced cardiac hypertrophy in cultured neonatal rat heart cells. Eur J Pharmacol. 1999; 376: 139–148.[CrossRef][Medline] [Order article via Infotrieve]
97. Luo JD, Xie F, Zhang WW, et al. Simvastatin inhibits noradrenaline-induced hypertrophy of cultured neonatal rat cardiomyocytes. Br J Pharmacol. 2001; 132: 159–164.[CrossRef][Medline] [Order article via Infotrieve]
98. Luo JD, Zhang WW, Zhang GP, et al. Simvastatin inhibits cardiac hypertrophy and angiotensin-converting enzyme activity in rats with aortic stenosis. Clin Exp Pharmacol Physiol. 1999; 26: 903–908.[CrossRef][Medline] [Order article via Infotrieve]
99. Dechend R, Fiebeler A, Park JK, et al. Amelioration of angiotensin II-induced cardiac injury by a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Circulation. 2001; 104: 576–581.
100. Hayashidani S, Tsutsui H, Shiomi T, et al. Fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, attenuates left ventricular remodeling and failure after experimental myocardial infarction. Circulation. 2002; 105: 868–873.
101. Patel R, Nagueh SF, Tsybouleva N, et al. Simvastatin induces regression of cardiac hypertrophy and fibrosis and improves cardiac function in a transgenic rabbit model of human hypertrophic cardiomyopathy. Circulation. 2001; 104: 317–324.
102. Takemoto M, Node K, Nakagami H, et al. Statins as antioxidant therapy for preventing cardiac myocyte hypertrophy. J Clin Invest. 2001; 108: 1429–1437.[CrossRef][Medline] [Order article via Infotrieve]
103. Laufs U, Kilter H, Konkol C, et al. Impact of HMG CoA reductase inhibition on small GTPases in the heart. Cardiovasc Res. 2002; 53: 911–920.
104. Sadoshima J, Izumo S. The cellular and molecular response to cardiac myocytes to mechanical stress. Annu Rev Physiol. 1997; 59: 551–571.[CrossRef][Medline] [Order article via Infotrieve]
105. Zou Y, Takano H, Akazawa H, et al. Molecular and cellular mechanisms of mechanical stress-induced cardiac hypertrophy. Endocr J. 2002; 49: 1–13.[Medline] [Order article via Infotrieve]
106. Brancaccio M, Fratta L, Notte A, et al. Melusin, a muscle-specific integrin beta(1)-interacting protein, is required to prevent cardiac failure in response to chronic pressure overload. Nat Med. 2003; 9: 68–75.[CrossRef][Medline] [Order article via Infotrieve]
107. Knoll R, Hoshijima M, Hoffman HM, et al. The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy. Cell. 2002; 111: 943–955.[CrossRef][Medline] [Order article via Infotrieve]
108. Frey N, Richardson JA, Olson EN. Calsarcins, a novel family of sarcomeric calcineurin-binding proteins. Proc Natl Acad Sci U S A. 2000; 97: 14632–14637.
109. Takewaki S, Kuroo M, Hiroi Y, et al. Activation of Na+-H+ antiporter (Nhe-1) gene expression during growth, hypertrophy and proliferation of the rabbit cardiovascular system. J Mol Cell Cardiol. 1995; 27: 729–742.[Medline] [Order article via Infotrieve]
110. Yoshida H, Karmazyn M. Na+/H+ exchange inhibition attenuates hypertrophy and heart failure in 1-wk postinfarction rat myocardium. Am J Physiol Heart Circ Physiol. 2000; 278: H300–H304.
111. Cingolani HE, de Hurtado MCC. Na+-H+ exchanger inhibition: a new antihypertrophic tool. Circ Res. 2002; 90: 751–753.
112. Kusumoto K, Haist JV, Karmazyn M. Na+/H+ exchange inhibition reduces hypertrophy and heart failure after myocardial infarction in rats. Am J Physiol Heart Circ Physiol. 2001; 280: H738–H745.
113. Engelhardt S, Hein L, Keller U, et al. Inhibition of Na+-H+ exchange prevents hypertrophy, fibrosis, and heart failure in {beta}1-adrenergic receptor transgenic mice. Circ Res. 2002; 90: 814–819.
114. Rockman HA, Chien KR, Choi DJ, et al. Expression of a beta-adrenergic receptor kinase 1 inhibitor prevents the development of myocardial failure in gene-targeted mice. Proc Natl Acad Sci U S A. 1998; 95: 7000–7005.
115. del Monte F, Williams E, Lebeche D, et al. Improvement in survival and cardiac metabolism after gene transfer of sarcoplasmic reticulum Ca2+-ATPase in a rat model of heart failure. Circulation. 2001; 104: 1424–1429.
116. Schmidt U, del Monte F, Miyamoto MI, et al. Restoration of diastolic function in senescent rat hearts through adenoviral gene transfer of sarcoplasmic reticulum Ca2+-ATPase. Circulation. 2000; 101: 790–796.
117. Most P, Remppis A, Pleger ST, et al. Transgenic overexpression of the Ca2+-binding protein S100A1 in the heart leads to increased in vivo myocardial contractile performance. J Biol Chem. 2003; 278: 33809–33817.
118. Luo W, Grupp IL, Harrer J, et al. Targeted ablation of the phospholamban gene is associated with markedly enhanced myocardial contractility and loss of beta-agonist stimulation. Circ Res. 1994; 75: 401–409.
119. del Monte F, Harding SE, Dec GW, et al. Targeting phospholamban by gene transfer in human heart failure. Circulation. 2002; 105: 904–907.
120. Minamisawa S, Hoshijima M, Chu GX, et al. Chronic phospholamban-sarcoplasmic reticulum calcium ATPase interaction is the critical calcium cycling defect in dilated cardiomyopathy. Cell. 1999; 99: 313–322.[CrossRef][Medline] [Order article via Infotrieve]
121. Hoshijima M, Ikeda Y, Iwanaga Y, et al. Chronic suppression of heart-failure progression by a pseudophosphorylated mutant of phospholamban via in vivo cardiac rAAV gene delivery. Nat Med. 2002; 8: 864–871.[Medline] [Order article via Infotrieve]
122. Sato Y, Kiriazis H, Yatani A, et al. Rescue of contractile parameters and myocyte hypertrophy in calsequestrin overexpressing myocardium by phospholamban ablation. J Biol Chem. 2001; 276: 9392–9399.
123. Freeman K, Lerman I, Kranias EG, et al. Alterations in cardiac adrenergic signaling and calcium cycling differentially affect the progression of cardiomyopathy. J Clin Invest. 2001; 107: 967–974.[Medline] [Order article via Infotrieve]
124. Song Q, Schmidt AG, Hahn HS, et al. Rescue of cardiomyocyte dysfunction by phospholamban ablation does not prevent ventricular failure in genetic hypertrophy. J Clin Invest. 2003; 111: 859–867.[CrossRef][Medline] [Order article via Infotrieve]
125. Schmitt JP, Kamisago M, Asahi M, et al. Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban. Science. 2003; 299: 1410–1413.
126. Haghighi K, Kolokathis F, Pater L, et al. Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human. J Clin Invest. 2003; 111: 869–876.[CrossRef][Medline] [Order article via Infotrieve]
127. Scheuer J, Malhotra A, Hirsch C, et al. Physiological cardiac hypertrophy corrects protein abnormalities associated with pathologic hypertrophy in rats. J Clin Invest. 1982; 70: 1300–1305.[Medline] [Order article via Infotrieve]
128. Iemitsu M, Miyauchi T, Maeda S, et al. Physiological and pathological cardiac hypertrophy induce different molecular phenotypes in the rat. Am J Physiol Regul Integr Comp Physiol. 2001; 281: R2029–R2036.
129. Diffee GM, Seversen EA, Stein TD, et al. Microarray expression analysis of effects of exercise training: increase in atrial MLC-1 in rat ventricles. Am J Physiol Heart Circ Physiol. 2003; 284: H830–H837.
130. Kinugawa K, Yonekura K, Ribeiro RCJ, et al. Regulation of thyroid hormone receptor isoforms in physiological and pathological cardiac hypertrophy. Circ Res. 2001; 89: 591–598.
131. Calderone A, Takahashi N, Izzo NJ Jr, et al. Pressure- and volume-induced left ventricular hypertrophies are associated with distinct myocyte phenotypes and differential induction of peptide growth factor mRNAs. Circulation. 1995; 92: 2385–2390.
132. Kjeldsen SE, Dahlöf B, Devereux RB, et al, for the LIFE Study Group. Effects of losartan on cardiovascular morbidity and mortality in patients with isolated systolic hypertension and left ventricular hypertrophy. JAMA. 2002; 288: 1491–1498.
133. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000; 342: 145–153.
134. Mathew J, Sleight P, Lonn E, et al. Reduction of cardiovascular risk by regression of electrocardiographic markers of left ventricular hypertrophy by the angiotensin-converting enzyme inhibitor ramipril. Circulation. 2001; 104: 1615–1621.
135. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) [published erratum appears in JAMA 2003;289:178]. JAMA. 2002; 288: 2981–2997.
136. Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial Research Group. Diuretic versus -blocker as first-step antihypertensive therapy: final results from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Hypertension. 2003; 42: 239–246.
137. Senbonmatsu T, Ichihara S, Price E, et al. Evidence for angiotensin II type 2 receptor-mediated cardiac myocyte enlargement during in vivo pressure overload. J Clin Invest. 2000; 106: R25–R29.[Medline] [Order article via Infotrieve]
138. Bartunek J, Weinberg EO, Tajima M, et al. Chronic.NG-nitro-L-arginine methyl ester-induced hypertension: novel molecular adaptation to systolic load in absence of hypertrophy. Circulation. 2000; 101: 423–429.
139. Ichihara S, Senbonmatsu T, Price E, et al. Angiotensin II type 2 receptor is essential for left ventricular hypertrophy and cardiac fibrosis in chronic angiotensin II-induced hypertension. Circulation. 2001; 104: 346–351.
140. Uozumi H, Hiroi Y, Zou Y, et al. gp130 plays a critical role in pressure overload-induced cardiac hypertrophy. J Biol Chem. 2001; 276: 23115–23119.
141. Shioi T, McMullen JR, Tarnavski O, et al. Rapamycin attenuates load-induced cardiac hypertrophy in mice. Circulation. 2003; 107: 1664–1670.
142. Hirota H, Chen J, Betz UAK, et al. Loss of a gp130 cardiac muscle cell survival pathway is a critical event in the onset of heart failure during biomechanical stress. Cell. 1999; 97: 189–198.[CrossRef][Medline] [Order article via Infotrieve]
143. Rogers JH, Tamirisa P, Kovacs A, et al. RGS4 causes increased mortality and reduced cardiac hypertrophy in response to pressure overload. J Clin Invest. 1999; 104: 567–576.[Medline] [Order article via Infotrieve]
144. Badorff C, Ruetten H, Mueller S, et al. Fas receptor signaling inhibits glycogen synthase kinase 3 beta and induces cardiac hypertrophy following pressure overload. J Clin Invest. 2002; 109: 373–381.[CrossRef][Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  A. Sengupta, J. D. Molkentin, and K. E. Yutzey FoxO Transcription Factors Promote Autophagy in Cardiomyocytes J. Biol. Chem., October 9, 2009; 284(41): 28319 - 28331. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Li, X.-L. Wei, L.-L. Meng, M.-G. Chi, J.-Q. Yan, X.-Y. Ma, Y.-S. Jia, L. Liang, H.-T. Yan, and J.-Q. Zheng Involvement of Tissue Transglutaminase in Endothelin 1-Induced Hypertrophy in Cultured Neonatal Rat Cardiomyocytes Hypertension, October 1, 2009; 54(4): 839 - 844. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. MacDonnell, J. Weisser-Thomas, H. Kubo, M. Hanscome, Q. Liu, N. Jaleel, R. Berretta, X. Chen, J. H. Brown, A.-K. Sabri, et al. CaMKII Negatively Regulates Calcineurin-NFAT Signaling in Cardiac Myocytes Circ. Res., August 14, 2009; 105(4): 316 - 325. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Kuhn, D. Frank, R. Will, C. Jaschinski, R. Frauen, H. A. Katus, and N. Frey DYRK1A Is a Novel Negative Regulator of Cardiomyocyte Hypertrophy J. Biol. Chem., June 19, 2009; 284(25): 17320 - 17327. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Singh, S. M. Manda, D. Sikder, M. J. Birrer, B. A. Rothermel, D. J. Garry, and P. P. A. Mammen Calcineurin Activates Cytoglobin Transcription in Hypoxic Myocytes J. Biol. Chem., April 17, 2009; 284(16): 10409 - 10421. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. S. Willis, M. Rojas, L. Li, C. H. Selzman, R.-H. Tang, W. E. Stansfield, J. E. Rodriguez, D. J. Glass, and C. Patterson Muscle ring finger 1 mediates cardiac atrophy in vivo Am J Physiol Heart Circ Physiol, April 1, 2009; 296(4): H997 - H1006. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. La Gerche, A. J. Taylor, and D. L. Prior Athlete's Heart: The Potential for Multimodality Imaging to Address the Critical Remaining Questions. J. Am. Coll. Cardiol. Img., March 1, 2009; 2(3): 350 - 363. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Cai, F.-F. Yi, L. Yang, D.-F. Shen, Q. Yang, A. Li, A. K. Ghosh, Z.-Y. Bian, L. Yan, Q.-Z. Tang, et al. Targeted Expression of Receptor-Associated Late Transducer Inhibits Maladaptive Hypertrophy via Blocking Epidermal Growth Factor Receptor Signaling Hypertension, March 1, 2009; 53(3): 539 - 548. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Cambronero, F. Marin, V. Roldan, D. Hernandez-Romero, M. Valdes, and G. Y.H. Lip Biomarkers of pathophysiology in hypertrophic cardiomyopathy: implications for clinical management and prognosis Eur. Heart J., January 9, 2009; (2009) ehn538v1. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. A. Rothermel and J. A. Hill Autophagy in Load-Induced Heart Disease Circ. Res., December 5, 2008; 103(12): 1363 - 1369. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Zamilpa and M. L. Lindsey AMP Activated Protein Kinase 2 Protection During Hypertension-Induced Hypertrophy: A Common Mediator in the Signaling Crossroads Hypertension, November 1, 2008; 52(5): 813 - 815. [Full Text] [PDF]
|
|
|
|
|
|
E. van Rooij, W. S. Marshall, and E. N. Olson Toward MicroRNA-Based Therapeutics for Heart Disease: The Sense in Antisense Circ. Res., October 24, 2008; 103(9): 919 - 928. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Friehs Proteasome inhibition in hypertrophied myocardium Am J Physiol Heart Circ Physiol, October 1, 2008; 295(4): H1373 - H1374. [Full Text] [PDF]
|
|
|
|
 |
|
 C.-H. Chu, B.-S. Tzang, L.-M. Chen, C.-H. Kuo, Y.-C. Cheng, L.-Y. Chen, F.-J. Tsai, C.-H. Tsai, W.-W. Kuo, and C.-Y. Huang IGF-II/mannose-6-phosphate receptor signaling induced cell hypertrophy and atrial natriuretic peptide/BNP expression via G{alpha}q interaction and protein kinase C-{alpha}/CaMKII activation in H9c2 cardiomyoblast cells J. Endocrinol., May 1, 2008; 197(2): 381 - 390. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. P. Alibin, M. A. Kopilas, and H. D. I. Anderson Suppression of Cardiac Myocyte Hypertrophy by Conjugated Linoleic Acid: ROLE OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS {alpha} AND {gamma} J. Biol. Chem., April 18, 2008; 283(16): 10707 - 10715. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Jacobshagen, M. Gruber, N. Teucher, A. G. Schmidt, B. W. Unsold, K. Toischer, P. Nguyen Van, L. S. Maier, H. Kogler, and G. Hasenfuss Celecoxib modulates hypertrophic signalling and prevents load-induced cardiac dysfunction Eur J Heart Fail, April 1, 2008; 10(4): 334 - 342. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Degousee, S. Fazel, D. Angoulvant, E. Stefanski, S.-C. Pawelzik, M. Korotkova, S. Arab, P. Liu, T. F. Lindsay, S. Zhuo, et al. Microsomal Prostaglandin E2 Synthase-1 Deletion Leads to Adverse Left Ventricular Remodeling After Myocardial Infarction Circulation, April 1, 2008; 117(13): 1701 - 1710. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Hill and E. N. Olson Cardiac Plasticity N. Engl. J. Med., March 27, 2008; 358(13): 1370 - 1380. [Full Text] [PDF]
|
|
|
|
|
|
J. B. Pillai, M. Chen, S. B. Rajamohan, S. Samant, V. B. Pillai, M. Gupta, and M. P. Gupta Activation of SIRT1, a class III histone deacetylase, contributes to fructose feeding-mediated induction of the {alpha}-myosin heavy chain expression Am J Physiol Heart Circ Physiol, March 1, 2008; 294(3): H1388 - H1397. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Hein, S. Kostin, and J. Schaper mRNA cargo no longer on time Am J Physiol Heart Circ Physiol, March 1, 2008; 294(3): H1130 - H1132. [Full Text] [PDF]
|
|
|
|
 |
|
 M. Colella, F. Grisan, V. Robert, J. D. Turner, A. P. Thomas, and T. Pozzan Ca2+ oscillation frequency decoding in cardiac cell hypertrophy: Role of calcineurin/NFAT as Ca2+ signal integrators PNAS, February 26, 2008; 105(8): 2859 - 2864. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Frank, C. Kuhn, B. Brors, C. Hanselmann, M. Ludde, H. A. Katus, and N. Frey Gene Expression Pattern in Biomechanically Stretched Cardiomyocytes: Evidence for a Stretch-Specific Gene Program Hypertension, February 1, 2008; 51(2): 309 - 318. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Chen, J. Zhang, T. X. Gan, Y. Chen-Izu, J. D. Hasday, M. Karmazyn, C. W. Balke, and S. M. Scharf Left ventricular dysfunction and associated cellular injury in rats exposed to chronic intermittent hypoxia J Appl Physiol, January 1, 2008; 104(1): 218 - 223. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. F. Padera Jr. and F. J. Schoen Pathology of Cardiac Surgery Card. Surg. Adult, January 1, 2008; 3(2008): 111 - 178. [Full Text]
|
|
|
|
 |
|
 J. Freeling, K. Wattier, C. LaCroix, and Y.-F. Li Neostigmine and pilocarpine attenuated tumour necrosis factor {alpha} expression and cardiac hypertrophy in the heart with pressure overload Exp Physiol, January 1, 2008; 93(1): 75 - 82. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Frank, C. Kuhn, M. van Eickels, D. Gehring, C. Hanselmann, S. Lippl, R. Will, H. A. Katus, and N. Frey Calsarcin-1 Protects Against Angiotensin-II Induced Cardiac Hypertrophy Circulation, November 27, 2007; 116(22): 2587 - 2596. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. MacDonnell, H. Kubo, D. M. Harris, X. Chen, R. Berretta, M. F. Barbe, S. Kolwicz, P. O. Reger, A. Eckhart, B. F. Renna, et al. Calcineurin inhibition normalizes beta-adrenergic responsiveness in the spontaneously hypertensive rat Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H3122 - H3129. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Loyer, P. Oliviero, T. Damy, E. Robidel, F. Marotte, C. Heymes, and J.-L. Samuel Effects of sex differences on constitutive nitric oxide synthase expression and activity in response to pressure overload in rats Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H2650 - H2658. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. S. Buys, M. J. Raher, S. L. Blake, T. G. Neilan, A. R. Graveline, J. J. Passeri, M. Llano, T. M. Perez-Sanz, F. Ichinose, S. Janssens, et al. Cardiomyocyte-restricted restoration of nitric oxide synthase 3 attenuates left ventricular remodeling after chronic pressure overload Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H620 - H627. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Appert-Collin, S. Cotecchia, M. Nenniger-Tosato, T. Pedrazzini, and D. Diviani The A-kinase anchoring protein (AKAP)-Lbc-signaling complex mediates {alpha}1 adrenergic receptor-induced cardiomyocyte hypertrophy PNAS, June 12, 2007; 104(24): 10140 - 10145. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-L. Li, Z.-G. She, T.-B. Li, A.-B. Wang, Q. Yang, Y.-S. Wei, Y.-G. Wang, and D.-P. Liu Overexpression of Myofibrillogenesis Regulator-1 Aggravates Cardiac Hypertrophy Induced by Angiotensin II in Mice Hypertension, June 1, 2007; 49(6): 1399 - 1408. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. E. Hannigan, J. G. Coles, and S. Dedhar Integrin-Linked Kinase at the Heart of Cardiac Contractility, Repair, and Disease Circ. Res., May 25, 2007; 100(10): 1408 - 1414. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Fisch, S. Gray, S. Heymans, S. M. Haldar, B. Wang, O. Pfister, L. Cui, A. Kumar, Z. Lin, S. Sen-Banerjee, et al. Kruppel-like factor 15 is a regulator of cardiomyocyte hypertrophy PNAS, April 24, 2007; 104(17): 7074 - 7079. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Schillinger, C. Christians, S. Sossalla, N. Teucher, P. Nguyen Van, H. Kogler, O. Zeitz, and G. Hasenfuss {alpha}1-adrenergic stress induces downregulation of Na+/Ca2+ exchanger in myocardial preparations from rabbits at physiological preload Eur J Heart Fail, April 1, 2007; 9(4): 329 - 335. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Fielitz, S. Philipp, L. R. Herda, E. Schuch, B. Pilz, C. Schubert, V. Gunzler, R. Willenbrock, and V. Regitz-Zagrosek Inhibition of prolyl 4-hydroxylase prevents left ventricular remodelling in rats with thoracic aortic banding Eur J Heart Fail, April 1, 2007; 9(4): 336 - 342. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Lemmens, V. F.M. Segers, M. Demolder, M. Michiels, P. Van Cauwelaert, and G. W. De Keulenaer Endogenous inhibitors of hypertrophy in concentric versus eccentric hypertrophy Eur J Heart Fail, April 1, 2007; 9(4): 352 - 356. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. V. Alvarez, D. E. Johnson, D. Sowah, D. Soliman, P. E. Light, Y. Xia, M. Karmazyn, and J. R. Casey Carbonic anhydrase inhibition prevents and reverts cardiomyocyte hypertrophy J. Physiol., February 15, 2007; 579(1): 127 - 145. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. G. Dickhout and R. C. Austin Proteasomal Regulation of Cardiac Hypertrophy: Is Demolition Necessary for Building? Circulation, October 24, 2006; 114(17): 1796 - 1798. [Full Text] [PDF]
|
|
|
|
|
|
J. B. Pillai, M. Gupta, S. B. Rajamohan, R. Lang, J. Raman, and M. P. Gupta Poly(ADP-ribose) polymerase-1-deficient mice are protected from angiotensin II-induced cardiac hypertrophy Am J Physiol Heart Circ Physiol, October 1, 2006; 291(4): H1545 - H1553. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Hannenhalli, M. E. Putt, J. M. Gilmore, J. Wang, M. S. Parmacek, J. A. Epstein, E. E. Morrisey, K. B. Margulies, and T. P. Cappola Transcriptional Genomics Associates FOX Transcription Factors With Human Heart Failure Circulation, September 19, 2006; 114(12): 1269 - 1276. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. G. Ni, K. Berenji, N. Wang, M. Oh, N. Sachan, A. Dey, J. Cheng, G. Lu, D. J. Morris, D. H. Castrillon, et al. Foxo Transcription Factors Blunt Cardiac Hypertrophy by Inhibiting Calcineurin Signaling Circulation, September 12, 2006; 114(11): 1159 - 1168. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Srivastava and S. Yu Stretching to meet needs: integrin-linked kinase and the cardiac pump Genes & Dev., September 1, 2006; 20(17): 2327 - 2331. [Full Text] [PDF]
|
|
|
|
 |
|
 G. Liu and F. Daneshgari Temporal diabetes- and diuresis-induced remodeling of the urinary bladder in the rat Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2006; 291(3): R837 - R843. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. London Natriuretic Peptides and Cardiac Hypertrophy J. Am. Coll. Cardiol., August 1, 2006; 48(3): 506 - 507. [Full Text] [PDF]
|
|
|
|
 |
|
 X. Chen, S. P. Shevtsov, E. Hsich, L. Cui, S. Haq, M. Aronovitz, R. Kerkela, J. D. Molkentin, R. Liao, R. N. Salomon, et al. The {beta}-Catenin/T-Cell Factor/Lymphocyte Enhancer Factor Signaling Pathway Is Required for Normal and Stress-Induced Cardiac Hypertrophy Mol. Cell. Biol., June 15, 2006; 26(12): 4462 - 4473. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Kong, P. Tannous, G. Lu, K. Berenji, B. A. Rothermel, E. N. Olson, and J. A. Hill Suppression of Class I and II Histone Deacetylases Blunts Pressure-Overload Cardiac Hypertrophy Circulation, June 6, 2006; 113(22): 2579 - 2588. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-M. Zhang, J. Bo, G. E. Taffet, J. Chang, J. Shi, A. K. Reddy, L. H. Michael, M. D. Schneider, M. L. Entman, R. J. Schwartz, et al. Targeted deletion of ROCK1 protects the heart against pressure overload by inhibiting reactive fibrosis FASEB J, May 1, 2006; 20(7): 916 - 925. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Perrino and H. A. Rockman GATA4 and the Two Sides of Gene Expression Reprogramming Circ. Res., March 31, 2006; 98(6): 715 - 716. [Full Text] [PDF]
|
|
|
|
|
|
P. M. Okin, R. B. Devereux, E. Gerdts, S. M. Snapinn, K. E. Harris, S. Jern, S. E. Kjeldsen, S. Julius, J. M. Edelman, L. H. Lindholm, et al. Impact of Diabetes Mellitus on Regression of Electrocardiographic Left Ventricular Hypertrophy and the Prediction of Outcome During Antihypertensive Therapy: The Losartan Intervention For Endpoint (LIFE) Reduction in Hypertension Study Circulation, March 28, 2006; 113(12): 1588 - 1596. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Mitchell, A. Ota, W. Foster, B. Zhang, Z. Fang, S. Patel, S. F. Nelson, S. Horvath, and Y. Wang Distinct gene expression profiles in adult mouse heart following targeted MAP kinase activation Physiol Genomics, March 13, 2006; 25(1): 50 - 59. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Zhang, T. Anger, J. Su, J. Hao, X. Xu, M. Zhu, A. Gach, L. Cui, R. Liao, and U. Mende Selective Loss of Fine Tuning of Gq/11 Signaling by RGS2 Protein Exacerbates Cardiomyocyte Hypertrophy J. Biol. Chem., March 3, 2006; 281(9): 5811 - 5820. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Razeghi and H. Taegtmeyer Cardiac Remodeling: UPS Lost in Transit Circ. Res., November 11, 2005; 97(10): 964 - 966. [Full Text] [PDF]
|
|
|
|
 |
|
 K. R. Sipido and D. Eisner Something old, something new: Changing views on the cellular mechanisms of heart failure Cardiovasc Res, November 1, 2005; 68(2): 167 - 174. [Full Text] [PDF]
|
|
|
|
|
|
G.-L. Wang, G.-X. Wang, S. Yamamoto, L. Ye, H. Baxter, J. R Hume, and D. Duan Molecular mechanisms of regulation of fast-inactivating voltage-dependent transient outward K+ current in mouse heart by cell volume changes J. Physiol., October 15, 2005; 568(2): 423 - 443. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. A. Rothermel, K. Berenji, P. Tannous, W. Kutschke, A. Dey, B. Nolan, K.-D. Yoo, E. Demetroulis, M. Gimbel, B. Cabuay, et al. Differential activation of stress-response signaling in load-induced cardiac hypertrophy and failure Physiol Genomics, September 21, 2005; 23(1): 18 - 27. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Kupari, H. Turto, and J. Lommi Left ventricular hypertrophy in aortic valve stenosis: preventive or promotive of systolic dysfunction and heart failure? Eur. Heart J., September 1, 2005; 26(17): 1790 - 1796. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. P.J. Buermans and W. J. Paulus Iconoclasts topple adaptive myocardial hypertrophy in aortic stenosis Eur. Heart J., September 1, 2005; 26(17): 1697 - 1699. [Full Text] [PDF]
|
|
|
|
|
|
J. Yoshioka, R. N. Prince, H. Huang, S. B. Perkins, F. U. Cruz, C. MacGillivray, D. A. Lauffenburger, and R. T. Lee Cardiomyocyte hypertrophy and degradation of connexin43 through spatially restricted autocrine/paracrine heparin-binding EGF PNAS, July 26, 2005; 102(30): 10622 - 10627. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Berenji, M. H. Drazner, B. A. Rothermel, and J. A. Hill Does load-induced ventricular hypertrophy progress to systolic heart failure? Am J Physiol Heart Circ Physiol, July 1, 2005; 289(1): H8 - H16. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Secko Straight to the heart with Viagra Can. Med. Assoc. J., April 12, 2005; 172(8): 993 - 993. [Full Text] [PDF]
|
|
|
|
|
|
J. B. Pillai, H. M. Russell, J. Raman, V. Jeevanandam, and M. P. Gupta Increased expression of poly(ADP-ribose) polymerase-1 contributes to caspase-independent myocyte cell death during heart failure Am J Physiol Heart Circ Physiol, February 1, 2005; 288(2): H486 - H496. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Graf and P. Stawowy Osteopontin: A Protective Mediator of Cardiac Fibrosis? Hypertension, December 1, 2004; 44(6): 809 - 810. [Full Text] [PDF]
|
|
|
|
|
|
M. Sano and M. D. Schneider Cyclin-Dependent Kinase-9: An RNAPII Kinase at the Nexus of Cardiac Growth and Death Cascades Circ. Res., October 29, 2004; 95(9): 867 - 876. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Chang, T. A. McKinsey, C. L. Zhang, J. A. Richardson, J. A. Hill, and E. N. Olson Histone Deacetylases 5 and 9 Govern Responsiveness of the Heart to a Subset of Stress Signals and Play Redundant Roles in Heart Development Mol. Cell. Biol., October 1, 2004; 24(19): 8467 - 8476. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||