Published online before print August 12, 2008, doi: 10.1161/CIRCULATIONAHA.107.760488
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(Circulation. 2008;118:934-946.)
© 2008 American Heart Association, Inc.
Molecular Cardiology |
Quantitative Control of Adaptive Cardiac Hypertrophy by Acetyltransferase p300
From the University of Miami School of Medicine, Departments of Molecular and Cellular Pharmacology (J.Q.W., L.A.S., J.M.M., M.P., T.I.S., K.A.W., N.H.B.), Medicine (N.H.B.), and Pediatrics (N.H.B.), Miami, Fla.
Correspondence to Nanette H. Bishopric, MD, RMSB 6038, PO Box 016189 (R-189), 1600 NW 10th Ave RMSB 6026, Miami, FL 33101. E-mail n.bishopric{at}miami.edu
Received January 28, 2008; accepted June 27, 2008.
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Abstract |
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Background— Acetyltransferase p300 is essential for cardiac development and is thought to be involved in cardiac myocyte growth through MEF2- and GATA4-dependent transcription. However, the importance of p300 in the modulation of cardiac growth in vivo is unknown.
Methods and Results— Pressure overload induced by transverse aortic coarctation, postnatal physiological growth, and human heart failure were associated with large increases in p300. Minimal transgenic overexpression of p300 (1.5- to 3.5-fold) induced striking myocyte and cardiac hypertrophy. Both mortality and cardiac mass were directly related to p300 protein dosage. Heterozygous loss of a single p300 allele reduced pressure overload–induced hypertrophy by 
50% and rescued the hypertrophic phenotype of p300 overexpressers. Increased p300 expression had no effect on total histone deacetylase activity but was associated with proportional increases in p300 acetyltransferase activity and acetylation of the p300 substrates histone 3 and GATA-4. Remarkably, a doubling of p300 levels was associated with the de novo acetylation of MEF2. Consistent with this, genes specifically upregulated in p300 transgenic hearts were highly enriched for MEF2 binding sites.
Conclusions— Small increments in p300 are necessary and sufficient to drive myocardial hypertrophy, possibly through acetylation of MEF2 and upstream of signals promoting phosphorylation or nuclear export of histone deacetylases. We propose that induction of myocardial p300 content is a primary rate-limiting event in the response to hemodynamic loading in vivo and that p300 availability drives and constrains adaptive myocardial growth. Specific reduction of p300 content or activity may diminish stress-induced hypertrophy and forestall the development of heart failure.
Key Words: acetylation • epigenetics • heart failure • hypertrophy • transcription
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Introduction |
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Cardiac hypertrophy in response to stress involves the enlargement of myocytes by the addition of contractile proteins.1 This process, largely under transcriptional control, involves sarcomeric gene induction within preexisting myocytes and a characteristic reversion to fetal protein isoforms affecting contractility, metabolism, and calcium handling.2–5 The mechanisms for coordinating this transcriptional response are incompletely understood.
Clinical Perspective p 946
Acetylation of histones and transcription factors promotes transcription by unpacking chromatin and facilitating protein-DNA interactions.6,7 Nuclear proteins can be acetylated by one of several histone/factor acetyltransferases (HATs), including E1A-associated nuclear protein p300 (p300), CREB-binding protein (CBP), and p300/CBP-associated factor (reviewed elsewhere8–10). The reverse reaction inhibits transcription and is performed by histone deacetylases (HDACs), a large protein family with at least 18 members and 3 distinct structural classes.11,12 HATs and HDACs play critical roles in cell proliferation, survival, growth, and differentiation and participate in cardiac myocyte growth and stress responses. Acetyltransferase p300 is required for cardiac myocyte gene expression,13,14 and p300 and/or CBP are involved in the growth of cultured cardiac myocytes in response to adrenergic stimulation.15 The role of HDACs in hypertrophy is more complex. Cardiac growth is potentiated by loss of either of the class II HDACs (HDAC-5 and HDAC-9), possibly because of their role in silencing MEF2.16,17 On the other hand, evidence suggests that certain HDACs promote hypertrophy.18–20 The identity and importance of HATs in cardiac growth remain unknown.
Despite their similar structure and expression patterns, acetyltransferases p300 and CBP have distinct functions and gene targets.21–26 Importantly, p300, not CBP, is specifically required for cardiac development. Deletion of p300 or inactivation of p300 acetyltransferase leads to heart failure and death at E9.5 to E11, with failure of myocardial cell proliferation.27 In contrast, 2 different groups have reported that CBP-null mice do not have cardiac abnormalities.21,28 Here, we report that p300 has an indispensable role in the cardiac adaptive response to pressure overload in the adult mouse. Hemodynamic loading induces a large, rapid, and sustained elevation of myocardial p300 levels. Transgenic p300 elevation directly mediated an adaptive hypertrophy that was associated with eventual decompensation. Genetic reduction of p300 limited both hypertrophy and the attendant risk of heart failure. Increased p300 was associated with de novo appearance of acetylated MEF2 and activation of MEF2-dependent genes, with no change in HDAC activity. We propose that hypertrophy in response to pressure overload is initiated by an increase in p300 levels and that p300 is the primary driver of both adaptive and maladaptive phases of cardiac hypertrophy in vivo through direct effects on MEF2 acetylation.
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Methods |
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Materials
CMVβp300 CHA, containing nucleotides 1134 to 8329 of p300 with a C-terminal hemagglutinin tag, was provided by Dr Richard Eckner. Monoclonal anti-p300 C-terminus and polyclonal anti–acetyl-lysine antibodies were obtained from the Upstate Group (Charlottesville, Va). Anti–acetyl-histone 3 was purchased from Cell Signaling Technology (Beverly, Mass). GATA4 (H-112) and MEF2 (C-21) antibodies were from Santa Cruz Biotechnology (Santa Cruz, Calif). HAT and HDAC assay kits were provided by BioVision Research Products (Mountain View, Calif).
Cell Culture
Cardiac myocytes were isolated from d1-3 Sprague-Dawley rat pups as previously described29 and plated on Nunc 2-well glass chamber slides in DMEM plus 5% FCS. On the next day, cells were transfected with Lipofectamine (Invitrogen, Carlsbad, Calif) with 1 µg expression vectors encoding p300 or green fluorescence protein or a blank pcDNA3.1 vector and were maintained in defined serum-free medium as previously described.30
Human Myocardial Samples
Myocardial tissue was obtained through the Human Cooperative Tissue Network and the Organ Procurement Center at the University of Miami under an Internal Review Board–approved research protocol. All tissues studied were harvested and placed on ice within 2 hours after death or surgical explantation. Anonymized data, including race, age, and cause of death, were obtained for all samples.
Induction of Cardiac Hypertrophy
All animal studies were conducted according to protocols approved by the University of Miami Animal Care and Use Committee. In vivo pressure overload was created in wild-type (WT) and genetically modified mice by creation of a surgical restriction in the transverse aorta between the origins of the right and left carotid arteries as described previously31 (see the Methods section in the online Data Supplement).
Generation and Maintenance of p300 Transgenic and Gene-Targeted Mice
Full-length human p300 cDNA was cloned directly in front of the murine 
-myosin heavy chain promoter.32 Mice heterozygous for a targeted p300 allele (p300–/+), the kind gift of Drs David Livingston and T.-P. Yao, were maintained on a C57Bl/6 background (see the supplemental Methods).
Histological and Morphometric Analyses
Standard hematoxylin and eosin, Masson’s trichrome, and Picrosirius Red staining protocols and a commercially available terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay kit (Cardiotacs, Trevigen, Gaithersburg, Md) were used for microscopic evaluation of myocardial tissue. Photomicrographs were obtained with a Nikon ES 400 microscope with a Pixera digital camera (Pixera, Los Gatos, Calif). Stereometric analysis used previously described methods33 (see the supplemental Methods).
RNA and Protein Analyses
Total RNA was isolated from left ventricular myocardium with Trizol (Molecular Research Center, Inc, Cincinnati, Ohio) and analyzed by Northern blot or real-time polymerase chain reaction (PCR) with TaqMan probes (Applied Biosystems, Foster City, Calif). Results were normalized to GAPDH (for real-time PCR) or 28S RNA (for Northern blots). Cell lysates were obtained from cultured myocytes or ventricular tissue and centrifuged at 8000g for 15 minutes to yield a supernatant containing cytosol/nucleosol. The cytosol/nucleosol and Triton-solubilized pellet fractions were subjected to immunoblotting and imaged by chemiluminescence with the Amersham ECL Western detection system (GE Healthcare Bio-Sciences, Piscataway, NJ).
In Silico Promoter Analysis
Two-color murine microarrays were used to identify p300-induced transcripts in p300 transgenic (p300tg) left ventricular myocardium at 1 month of age relative to WT littermates. The most significantly upregulated genes were further validated by real-time PCR. From this data set, 46 nonredundant promoters were extracted and analyzed for shared transcription factor binding sites with Gene2Promoter and MatInspector components of the Genomatix software suite (www.Genomatix.de).34 Identical analysis was performed on 50 transcripts chosen at random from targets identified as present but neither induced nor repressed by p300. Transcription factor site frequencies were compared in regulated versus unregulated gene promoters (see supplemental Data 1).
In Vivo Acetylation Assays
Transgenic and WT mouse hearts were analyzed for HDAC and total and p300-specific HAT activity with commercially available kits (BioVision) using immunoprecipitation with antibodies directed against p300, acetyl-histone 3 (Cell Signaling), or acetyl-lysine (Upstate), followed by immunodetection with histone 3, MEF2, and GATA4 (see the supplemental Methods) or the reverse.
Statistical Analysis
All sample mean and column comparisons for p300 protein levels and HAT activity across age and genotypes, individual mRNA transcripts, and other single parameters for WT and p300tg mice were performed with 1-way ANOVA, followed by the Student 2-tailed t test if significant differences were found; Bonferroni posttesting yielded similar results. Two-way ANOVA and Bonferroni correction were used for multiple comparisons among intervention groups and genotypes. Curves in the figures were analyzed and compared by use of linear regression or Kaplan-Meier product-limit analysis and Mante-Haenszel log-rank test for curve comparisons. Values of P<0.05 were considered significant. All statistical analyses were performed with Prism 4.0 statistical software for Macintosh (GraphPad, San Diego, Calif).
The authors had full access to and take responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
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Results |
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Regulation of p300 Levels During Normal and Pathological Myocardial Growth
Myocardial p300 protein levels in WT C57/Bl6 mice rose during the period of postnatal physiological hypertrophy, peaking at 2 months and declining thereafter (Figure 1A). Levels of p300 also increased during the hypertrophic response to norepinephrine or FBS in cultured neonatal rat cardiomyocytes29 (Figure 1B). Increased p300 RNA was detected between 24 to 72 hours after stimulation, whereas increased p300 protein levels appeared much earlier, suggesting an additional level of posttranscriptional regulation (Figure 1B).
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0.01 vs untreated samples. C, p300 expression is induced during TAC-mediated hypertrophy in vivo. Top, TAC induces hypertrophy. Hearts were removed at the indicated times after TAC or a sham operation as described in Methods. Normalized cardiac mass is the ratio of heart weight to tibia length. n=3; *P<0.05 for comparison of sham and TAC at each time point. Center, TAC induces p300 mRNA. Quantitative real-time PCR analysis of LV p300 mRNA levels after TAC. Values are given as the ratios of p300, GAPDH, and B-type natriuretic peptide (BNP) mRNA transcript levels in animals with and without TAC normalized to 18S RNA. Graph: n=3. Bottom, TAC induces p300 protein. Representative Western analysis of myocardial lysates from WT C57Bl/6 mice subjected to TAC or a sham operation for the indicated times. Blots were probed with monoclonal antibodies against p300 carboxy terminus (NM-11) or myosin heavy chain (HC). Sh indicates sham; Ao, aortic coarctation; TG, p300tg mouse heart. **P<0.0001 for comparison of sham and TAC at each time point. D, Increased myocardial p300 in human cardiomyopathy. Samples of human LV were obtained within 4 hours of death or explantation from subjects with and without heart disease (see
A model of pressure overload (transverse aortic coarctation [TAC]) was used to determine the association of p300 with cardiac growth in vivo. Moderate 45±3-mm Hg transverse aortic gradients induced hypertrophy within 3 days, increasing cardiac mass to 1.75 times control at 42 days (Figure 1C, top; P=0.015). In the same hearts, p300 mRNA increased >4-fold (TAC versus sham; n=3; P<0.05) within 2 hours, falling to baseline by 48 hours (Figure 1C, center). This was accompanied by a sustained and marked increase in p300 protein (9.72-fold of control at 48 hours; n=4; P<0.0001) that persisted for 
6 weeks (Figure 1C, bottom). In addition, p300-specific HAT activity was increased in mouse hearts 1 and 2 days after TAC (data not shown). Similar increases in p300 protein were seen in the hearts of rats subjected to 3 months of abdominal aortic coarctation and in rats with spontaneous hypertension heart failure after the onset of hypertension (data not shown).
The p300 levels also were increased in left ventricular tissue of subjects with ischemic, dilated, or unspecified end-stage cardiomyopathy compared with nonfailing controls (Figure 1D; n7 per group; P<0.0001 for dilated cardiomyopathy and P=0.0006 for ischemic cardiomyopathy versus nonfailing). Correspondingly, p300-specific HAT activity was increased 1.25-fold in failing versus nonfailing hearts (n=8; P=0.004; Figure 1D). All diseased hearts met the criteria for hypertrophy35 (Table 1).
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Doubling p300 Levels Induces Cardiac Hypertrophy
Cultured neonatal rat cardiomyocytes transfected with a p300 expression vector were substantially larger than those receiving a blank cytomegalovirus vector (Figure 2A), supporting a direct growth-promoting role. To confirm this finding in vivo, we generated 6 lines of mice with cardiac myocyte–specific expression of a human p300 transgene (see Methods). In p300tg mice, total p300 mRNA was increased by 5- to 6-fold (data not shown). Total p300 protein levels (endogenous plus transgenic) were strain dependent and increased between 1.5 and 7.5 times WT by 2 weeks of age in all lines (Table 2). All p300tg lines exhibited cardiac hypertrophy. In 3 low-expressing lines (1.5 to 3.7 times WT), normalized cardiac mass was 2.5 times WT by 3 months of age (Figure 2B). Hypertrophy was characterized by accumulation of sarcomeric protein and increased myofibrillar content (Figure 2C through 2H). Myocyte cross-sectional area in p300tg mice was more than double that of WT mice between 1 to 3 months, with no difference in connective tissue content (Figure 2I). Systolic function and ratio of wall thickness to chamber size were normal up to at least 6 months in these lines (Table 3). Proliferating cell nuclear antigen staining and Ki67 staining were negative for both WT and p300tg mice (not shown), arguing against significant hyperplasia in p300tg myocardium.
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Hypertrophy-associated transcripts, including skeletal -actin, β-myosin heavy chain, and A- and B-type natriuretic peptides, were upregulated in p300tg hearts by 1 month of age. Additional p300-sensitive transcripts included KCNE1, a potassium channel subunit; sarcomeric and structural proteins fibrillin-1, tropomodulin-3, and tropomyosin-1; and the mineralocorticoid receptor–generating enzyme 11-β-OH-steroid dehydrogenase (Figure 2J).
Haploinsufficiency for p300 Limits Hypertrophy
Mice with heterozygous loss of p300 (p300–/+), which express 50% of WT p300 protein levels,27 and their WT littermates were subjected to TAC or a sham operation as described above. Perioperative survival was 100% for both genotypes. TUNEL staining revealed no detectable apoptosis at baseline in either genotype. Transaortic gradients were measured for each animal before death at 18 days and 4 months. A marked reduction in both basal and stress-induced myocardial p300 levels in p300–/+ mice versus WT mice was seen at both time points. Induction of A-type natriuretic peptide and -actin transcripts was significantly lower in p300–/+ versus WT mice 18 days after TAC (Figure 3A and 3B). At 4 months, A-type natriuretic peptide levels remained elevated in WT mice but were not significantly increased in p300–/+ mice after TAC (Figure 3C). In addition, the mean TAC-induced increase in myocardial mass was 50% lower in p300–/+ mice (Figure 3D). The relationship between p300 and cardiac mass persisted at every workload measured (Figure 3E).
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=2-tailed P<0.0001).
p300 Dose Dependence of Hypertrophy and Heart Failure
Myocardial chamber geometry in p300tg mice evolved between 5 weeks and 10 months from a predominantly hypertrophic to a dilated configuration, as assessed by the ratio of chamber volume to wall thickness (Figure 4A). Heart mass was strongly associated with mortality risk (Figure 4B).
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Mortality was also strain dependent and strongly correlated with myocardial p300 levels as determined by Western analysis (Figure 4C and Table 2). In the 3 low-expressing lines, heart failure developed in most animals after 7 months of age, associated with reduced median survival of 36, 47, and 60 weeks (P<0.0001 versus WT). High-expressing lines (6.9 to 7.1 times WT) had markedly earlier onset of heart failure and shorter median survivals of 8 and 11.5 weeks (Figure 4C and Table 2). Increased apoptosis was detected only in 1 high-expressing line (data not shown). Parity also was a significant risk factor for death in that 100% of transgenic females died after 2 to 3 pregnancies with massive cardiomegaly (not shown).
Reduction of p300 Reduces Age-Dependent Hypertrophy and Heart Failure Mortality
A genetic rescue experiment was performed mating p300tg mice with p300-haploinsufficient mice. Four genotypes resulted with myocardial p300 levels directly proportional to p300 gene dosage (WT, transgenic, knockout, and transgenic/knockout, corresponding to WT/p300+/+, transgenic/p300+/+, WT/p300–/+, and transgenic/p300–/+; Figure 5A). Of 181 live births, 25% were WT/WT, 24% transgenic/WT, 18% WT/knockout, and 34% transgenic/knockout; these ratios suggest that cotransmission of the p300 transgene may have rescued some animals carrying the inactivated p300 allele. At 2 months of age, normalized heart mass did not differ among the groups, but substantial differences emerged by 8 months, closely paralleling p300 levels (Figure 5B). Mortality of transgenic mice was 80% at 12 months and was attributable entirely to heart failure. However, survival of p300tg mice carrying 1 p300-null allele (transgenic/knockout) was significantly better and halfway between that of WT and transgenic mice (Figure 5C). Heart weight and p300 levels also were halfway between those of the transgenic and WT mice (compare Figure 5A and 5B). Knockout mice had reduced survival (Figure 5C and data not shown), possibly attributable to p300 insufficiency in other organs but not the result of heart failure, heart malformation, or tumorigenesis. This phenotype was not reported in the original description of the line but emerged after extensive backcrossing into a C57/Bl6 background. The doubly modified mice had survival equivalent to the mice with a single defective p300 allele, indicating that excess deaths associated with the p300 transgene were rescued by loss of 1 endogenous p300 allele.
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p300 Selectively Targets MEF2-Containing Promoters During Hypertrophy In Vivo
A bioinformatics approach was to identify cis-regulatory elements enriched in p300-induced genes.34 Two sets of promoters from the same microarray analysis were compared: those associated with p300-induced transcripts and those associated with transcripts that were expressed at measurable but equal levels in both WT and transgenic hearts (p300 insensitive). Forty-six and 49 nonredundant promoters were extracted from these groups, respectively, and analyzed for the presence of consensus GATA4, MEF2, or NKX2.5 sites (see Methods and supplementary Data 1). All 3 elements were highly overrepresented relative to their genome-wide frequency (Table 4; P<0.005). There was no difference in the representation of NKX2.5 or GATA sites in p300-induced versus p300-insensitive promoter groups; NKX2.5 and GATA sites were present in 100% and 97.8% of both. In contrast, MEF2 sites were significantly enriched in p300-regulated promoters compared with the unregulated control group (Table 4; P=0.032).
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p300 Induction Switches MEF2 From an Inactive to an Active State
There was no difference in total cellular HDAC activities in myocardium from 1- to 2-month-old p300tg and WT mice (Figure 6A). However, p300-specific HAT activity was increased by 2.4-fold in transgenic mice, equal to the increase in total p300 protein (Figure 6B; P<0.0001). Consistent with this, total acetyl-lysine was increased by 47% (Figure 6C) and acetyl-histone 3 by 53% (Figure 6D). Ac-GATA4 was abundant in WT mice but was 60% higher in p300tg mice (Figure 6E; P=0.0002). In contrast, acetyl-MEF2 was absent in all WT hearts examined but readily detected in all p300tg hearts (Figure 6E).
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Discussion |
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p300, Decompensation, and Heart Failure
p300 is involved in a number of cell growth and survival processes in the cardiac myocyte.13–15,27,36–39 However, whether p300 plays a unique or indispensable role in hypertrophy in vivo has not been established. Here, we show that p300 is rapidly induced in response to hemodynamic stress, accompanied by increased p300 HAT activity, and that fractional increases and reductions in p300 have corresponding effects on myocardial growth. Other HATs such as CBP and p300/CBP-associated factor do not appear to compensate for partial p300 loss. Thus, p300 is an essential endogenous regulator of the cardiac hypertrophic response in vivo, and the induction of endogenous myocardial p300 by pressure loading is a requirement for hypertrophy and for both its compensatory and maladaptive sequelae.
Importantly, our mouse models show that both adaptive hypertrophy and heart failure risk correlate directly within a narrow physiological range of p300 levels. During the first 5 months of life, p300-driven hypertrophy is well tolerated and lacks features such as SERCA2 downregulation, fibrosis, and abnormal systolic function that are associated with end-stage heart failure. Despite this, most p300tg mice develop heart failure within a year, suggesting that heart failure is a byproduct of secondary factors related to the intensity and duration of the hypertrophic stimulus. Higher (>6-fold) levels of p300 expression were fatal sooner; similarly, Yanazume et al37 and Miyamoto et al40 found that a mouse line with 7-fold overexpression of p300 developed dilated cardiomyopathy and exhibited enhanced post–myocardial infarction remodeling. Thus, p300 can be seen as a molecular rheostat that determines the extent of hypertrophy along a continuum between compensation and decompensation.
MEF2 as a Critical Target of p300 in Hypertrophy
Although p300 has been reported to interact with many different transcription factors, 2 findings point to MEF2 as particularly important in hypertrophy. First, MEF2 but not NKX2.5 or GATA4 sites were significantly overrepresented in the promoters of p300-induced versus p300-unresponsive myocardial genes. As expected, both groups of transcripts were highly enriched for cardiac transcription factor binding sites, relative to promoters from the genome at large.41 Surprisingly, nearly 100% of transcripts expressed in the myocardium contained both NKX and GATA4 sites, suggesting that even "housekeeping" gene expression in the heart requires these tissue-specific factors. The selective representation of MEF2 sites in p300-induced genes is thus strong correlative evidence that MEF2 is preferentially enlisted in p300-initiated hypertrophy.
Second, p300 induction promotes a qualitative shift in the acetylation state of MEF2 in vivo. MEF2-dependent transcription is not regulated primarily by MEF2 supply but through posttranscriptional mechanisms, including association with the class II HDACs (HDAC-5 and -9).42 Association with HDACs is likely to be responsible for the near-complete deacetylation of MEF2 under basal conditions.43 Signal-dependent removal of HDACs from MEF2 has been proposed as a central mechanism for stress-induced hypertrophy.16 On the other hand, MEF2 can associate with p300 via its MADS domain44 and is acetylated and activated by p300.45,46 As we show here, a small increase in myocardial p300 can convert MEF2 from a basal deacetylated state to one in which it is acetylated and therefore active, suggesting that p300 HAT and HDAC activities are very closely balanced. By comparison, acetylation of myocardial GATA-4 is substantial under normal loading conditions in vivo and rises incrementally when p300 is elevated. These observations argue strongly for a specific role of MEF2 acetylation by p300 in driving the hypertrophy-associated gene expression program.
Induction of p300 Expression Initiates Hypertrophy
A large number of studies (reviewed elsewhere9,47,48) indicate that p300 levels are tightly limited in the cell and that transcription factors compete for access to this coactivator. Our data show that the stoichiometry of p300 is indeed a critical factor in the promotion of cardiac growth. Transgene-mediated doubling of p300 content was coupled to a proportionate increase in p300-specific HAT activity, confirming that p300 levels directly determine p300 enzymatic function. The prohypertrophic effects of p300 did not require experimental activation of other growth signals, suggesting that p300 is independent or at least upstream of these signals and associated phosphorylation events.49–53 Similarly, the p300-associated increase in MEF2 acetylation occurred in the absence of extracellular signals previously shown to promote dissociation of HDACs from MEF-2. These results support the view that p300 promotes hypertrophy upstream of HDAC signal–mediated nuclear export and degradation, which serve to further potentiate the effects of p300 (see the diagram in Figure 7). The regulatory mechanisms controlling the cellular supply of p300 remain to be elucidated.
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p300 as a Therapeutic Target
Hypertrophy is the stereotypical adaptive response of the myocardium to stress and is believed to normalize local wall stress and to enhance blood delivery in the face of increased demand. Questions remain about whether and to what extent hypertrophy is necessary for successful stress adaptation. Our data suggest that the duration and intensity of p300 elevation during hemodynamic loading may be major determinants of heart failure risk. If so, blunting the hypertrophic response mediated by p300 could reduce that risk without compromising short-term adaptation. Indeed, curcumin, a polyphenolic compound reported to have antioxidant, antitumor, and anti-HAT activity, was recently shown to blunt hypertrophy and to reduce the rate of decompensation in several rat and mouse models of heart failure.54,55 The concept of inhibiting p300 HAT is analogous to that of reducing angiotensin-converting enzyme or β-adrenergic agonist activity, both of which are increased in heart failure. Our findings also highlight the importance of monitoring the cardiovascular impact of drugs that potentiate p300 activity, including HDAC inhibitors currently being tested for use in cancer and autoimmune disorders.56
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Acknowledgments |
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We thank Richard Eckner for providing the p300 expression vectors and for helpful discussions. We also thank Andrew Kung for providing p300–/+ mice, John Kuluz for the use of hemodynamic monitoring equipment, Richard Bookman for assistance with transcription profiling, and Sandra Lemmon for critical comments on the manuscript.
Sources of Funding
This work was supported by grants from the National Institutes of Health (R01-HL71094 to Dr Bishopric, R01-HL44578 to Dr Webster), the Florida Heart Research Institute (to Dr Bishopric), the American Heart Association Florida/Puerto Rico Affiliate (to Dr Bishopric), and the Fondation Leducq (05-CVD-02 to Dr Bishopric). Dr Shehadeh is the recipient of a Ruth Kirschstein National Research Service Award from the National Heart, Lung, and Blood Institute.
Disclosures
None.
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The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.107.760488/DC1.
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