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(Circulation. 1998;97:1890-1892.)
© 1998 American Heart Association, Inc.

Editorials

Signaling Hypertrophy

How Many Switches, How Many Wires

Charles J. Homcy, MD

From COR Therapeutics, Inc, South San Francisco, Calif.

Correspondence to Charles J. Homcy, MD, Research and Development, COR Therapeutics, Inc, 256 E Grand Ave, South San Francisco, CA 94080.

Key Words: Editorials • hypertrophy • angiotensin • receptors • signal transduction

Despite the longstanding appreciation by cardiologists of its fundamental importance, the hypertrophic process nevertheless remains an enigma. Key questions have not been answered. What are the outside-in signals that initiate this process? How many pathways can communicate these signals? Do they all converge to trigger the same orchestrated inside-out cardiac response? Cardiac hypertrophy appears to encompass more than one phenotype, even at the cellular level. Is there a good form of hypertrophy (a beneficial myocyte response) versus bad hypertrophy (the dysfunctional response)? But with the heart, the situation is, of course, even more complicated. The architecture of this organ is an important determinant of function; hence, alteration of the normal geometry of the heart as a consequence of hypertrophy can have important consequences—again, some worse than others. The myocardium, particularly in the setting of severe hypertrophy, can pay a high price in terms of its requirements for both substrates and O₂.

Thus, it is no surprise that cardiologists are always eagerly awaiting the chance to turn the next page on this story, hoping to find the answers to the above questions. Over the past 50 years at least, cardiologists, physiologists, biochemists, pharmacologists, and now molecular biologists have worked to understand this process, with each discipline finding, of course, what it is best prepared to recognize. The molecular signals underlying the genesis of hypertrophy would be a wonderful prize to garner. How many switches are there? Do they connect to multiple sets of wires, and where do these wires terminate? In a study reported in this issue of Circulation,¹ one of the sharper tools of modern-day biology is used to sever the connections to one of these switches, the angiotensin II type IA receptor, which is the dominant angiotensin II type I receptor subtype in the murine heart. Harada et al¹ interrupted the integrity of the functional angiotensin II type IA receptor gene in mice by homologous recombination, thereby eliminating its function—an admirable target, indeed, the angiotensin II type I receptor, in that there is a wealth of data in animals and man validating the renin-angiotensin system as a key player in the regulation of cardiovascular homeostasis. The role of angiotensin II in cardiovascular pathophysiology has also been validated vis a vis the clear benefit of ACE inhibitors in obviating ventricular remodeling and progression to heart failure after myocardial injury. Angiotensin II antagonism, whether by ACE inhibition or by direct receptor blockade, prevents myocardial hypertrophy when used in the treatment of systemic hypertension, and clearly one important component of ventricular remodeling after myocardial injury is cellular hypertrophy.

Thus, the clinical and physiological data are there to argue that this is a critical switch, the angiotensin II type I receptor. But there is much more. Biochemists and molecular pharmacologists have also developed strong data to argue that this receptor is both necessary and possibly sufficient to generate the signal for a cardiac myocyte to initiate its hypertrophic program. First, cardiomyocytes express the angiotensin II type 1 receptor on their surface. Second, this receptor is linked via the heterotrimeric (ß subunits) GTP-binding regulatory protein G_q to a variety of effectors known to regulate calcium signaling within the cardiomyocyte. This occurs via G_q activation of the phospholipase C ß isoforms, which leads to an increase in inositol trisphosphate, which enhances calcium release from intracellular stores. Diacylglycerol levels are also increased as a result of phospholipase C cleavage of phosphatidylinositol 4,5-bisphosphate. Diacylglycerol directly activates protein kinase C. Together, calcium and protein kinase C are known to activate a subset of early response genes thought to be important in initiating the hypertrophic response.² G protein–linked receptors (GPLR) may also activate other effector pathways, which would be predicted to stimulate cardiac hypertrophy. G_q-linked receptors of the angiotensin II receptor type can signal activation of the mitogen-activated protein (MAP) kinases, also referred to as extracellular signal–related kinases, which are also turned on by growth factor receptors of the epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) type.^{3 4 5} MAP kinases can phosphorylate a variety of transcription factors, such as TCF/Elk-1, that activate genes required for cell growth and division.⁶ More recently, it has been shown that angiotensin II type I receptor activation, in certain cellular contexts, can also activate a parallel protein kinase pathway known as stress-activated protein kinase (or JUN kinase), which mediates cellular responses to any of a variety of stressful stimuli.⁷ The prototypical early response element AP-1, activated in part via phosphorylation of the transcription factors JUN and ATF-2 by stress-activated protein kinase, thereby participates in the initiation of cellular hypertrophy.⁸ Finally, the cardiocyte itself apparently has all the necessary machinery to trigger the activation of this receptor in response to cellular stretch (an in vitro simulation of ventricular overload). Sadoshima et al⁹ had previously demonstrated that angiotensin II is released by the cardiocyte in response to cellular stretch, thereby leading to receptor activation.

The Yazaki laboratory has now tested the hypothesis that eliminating the angiotensin II type IA receptor would abrogate the hypertrophic response to pressure overload given the autocrine loop described above. Surprisingly, in response to aortic constriction, the hearts of knockout mice exhibit the same degree of cardiac hypertrophy as wild type. That this pathway had been effectively eliminated was nevertheless confirmed by their demonstration that the infusion of subpressor doses of angiotensin II caused significant concentric hypertrophy in wild-type mice but not in knockout mice. What does this lead one to conclude? An obvious possibility is the existence of multiple switches. In fact, this would seem appropriate for a response that is so vital to the function of the heart. As with all organs, it must grow during early development, and for the adult organism to cope, the cardiocyte must have an adaptive capacity to deal with volume and pressure overload whether initiated by exertion or a pathological event. These multiple switches are likely themselves interconnected. One might also argue that having knocked this gene out from early embryogenesis would promote the use of compensatory mechanisms so that the knockout animal could effectively employ other pathways more efficiently than the wild-type animal. An example of this phenomenon has been reported by Nyui et al,¹⁰ who showed that angiotensinogen knockout myocytes readily activate the MAP kinase pathway in response to cellular stretch, whereas in wild-type myocytes, this response was significantly inhibited by angiotensin I receptor antagonists.

Examples of interconnectedness among different types of transmembrane switches are now readily available. The EGF receptor, a prototypical member of the tyrosine kinase growth factor family of receptors, can be activated, of course, by its natural ligand EGF. However, at least two other switches can use this receptor to facilitate activation of the MAP kinase pathway described earlier. GPLR activation can promote, in certain cellular contexts, phosphorylation and activation of the EGF receptor in the absence of growth factor ligation.¹¹ Thus, in a sense, the GPLR parasitizes the intracellular domain of the EGF receptor as a signaling scaffold, thus simulating EGF ligation itself. The mechanism underlying this process is not clearly defined. It has been proposed for G_i-linked receptors that the Gß dimer, released on GPLR activation, mediates the transactivation of the EGF receptor by a member of the Src family of nonreceptor tyrosine kinases.¹² In an analogous manner, growth hormone can also apparently use the EGF receptor to activate the phosphatidylinositol-3 (PI-3) kinase signaling pathway. The binding of growth hormone to its cellular receptor, which is a member of the cytokine receptor superfamily, leads to the activation of another type of nonreceptor tyrosine kinase, JAK2.¹³ Activated JAK2 in turn phosphorylates a single tyrosine residue on the intracellular domain of the EGF receptor to facilitate the binding of the regulatory subunit of PI-3 kinase and subsequent catalytic activation. Activation of the PI-3 kinase pathway leads to the stimulation of several enzymes that regulate both transcription and translation and thus would be predicted to play an important role in mediating the development of cellular hypertrophy.¹⁴ PI-3 kinase activation also triggers the membrane anchoring and stimulation of c-Akt (also known as PKB), a serine-threonine kinase that plays an important role in suppressing apoptosis.^{15 16} This presumably would have important implications for the hypertrophied heart.

The above examples include three types of transmembrane signaling devices: G protein–linked receptors of the angiotensin II type I, endothelin, and alpha-1 adrenergic receptor type, all of which have been linked to cellular hypertrophy; growth factor receptors containing intracellular tyrosine kinase domains of the EGF and PDGF type; and cytokine receptors that use cytosolic tyrosine kinases to transmit signals. Each of these receptor types has the capacity, in part via cross talk, to activate key signaling pathways in the cell, leading to growth. However, interactions of this sort clearly go well beyond these types of motifs. It would be reasonable to predict that a host of other switches also interact to turn on a common set of signaling pathways, depending on the cellular context being studied. These switches could encompass a variety of different molecular motifs, including ion channels, likely important transducers of the cellular response to stretch; free radical–stimulated pathways, such as those mediated by nitric oxide and reactive oxygen species; and molecules capable of responding to cellular adhesive interactions as exemplified by the integrin superfamily.¹⁷ It is not surprising then that such a fundamentally important response as hypertrophy might be called into play by a multitude of outside-in switches signaling via parallel and interconnected pathways within the cell to turn on growth. That this is likely true is underscored by the generation of a host of transgenic animal models over the past several years in which overexpression of a particular gene, often one thought to be important in outside-in signaling, has led to cardiac hypertrophy as a phenotype. These include overexpression of protein kinase C,¹⁸ G_s,¹⁹ and G_q,²⁰ to mention just a few.

It is likely, however, that there are "molecular phenotypic" differences underlying cardiac hypertrophy triggered by different stimuli: not all signals will use identical sets of switches and wires; therefore, different biochemical and transcriptional responses will result. It will be informative to catalog the "molecular phenotypes" of the various forms of cardiac hypertrophy, particularly those due to volume or pressure overload. A variety of recently developed techniques can rapidly and accurately characterize thousands of mRNAs expressed by a particular cell type by first "tagging" each species with a unique marker.²¹ It is then possible to determine whether either qualitative or quantitative differences in the cardiocyte mRNA expression pattern exist, for example, in the absence or presence of hypertrophy or between various forms of hypertrophy. Molecular biologists might thereby get a better handle on how to characterize the various processes that trigger hypertrophy and a better understanding of why their pathophysiological sequelae are different. In the past, medicine has progressed because an astute clinician identified that a syndrome or disease is actually comprised of multiple phenotypes. For example, that unique molecular defects would underlie distinct clinical phenotypes was predicted for the mucopolysaccharidoses before the actual genetic mutations involving the different enzymes needed for the catabolism of this class of molecules were identified. In the modern era, identification of multiple genetic mutations underlying the various forms of familial hypertrophic cardiomyopathy or the long-QT syndrome represents similar stories. Cardiac hypertrophy will certainly require the combined efforts of clinicians, physiologists, biochemists, molecular biologists, and geneticists to dissect its various phenotypes, and this will almost certainly have to be done at the molecular level. When finally achieved, the cardiac hypertrophies will have been identified and their different pathological sequelae ultimately defined. Until then, cardiac hypertrophy will remain an enigma, but the story is getting better all the time.

Footnotes

The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

References

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