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Quantitative control of adaptive cardiac hypertrophy by acetyltransferase p300.

ABSTRACT: 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.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 approximately 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.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.

SUBMITTER: Wei JQ

PROVIDER: S-EPMC2726266 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

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Quantitative control of adaptive cardiac hypertrophy by acetyltransferase p300.

Wei Jian Qin JQ Shehadeh Lina A LA Mitrani James M JM Pessanha Monica M Slepak Tatiana I TI Webster Keith A KA Bishopric Nanette H NH

Circulation 20080812 9

<h4>Background</h4>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.<h4>Methods and results</h4>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 p3 ...[more]

PMID: 18697823

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Project description:BackgroundDespite advances in the treatment of heart failure, mortality remains high, particularly in individuals with diabetes. Activated transforming growth factor beta (TGF-?) contributes to the pathogenesis of the fibrotic interstitium observed in diabetic cardiomyopathy. We hypothesized that high glucose enhances the activity of the transcriptional co-activator p300, leading to the activation of TGF-? via acetylation of Smad2; and that by inhibiting p300, TGF-? activity will be reduced and heart failure prevented in a clinically relevant animal model of diabetic cardiomyopathy.Methodsp300 activity was assessed in H9c2 cardiomyoblasts under normal glucose (5.6 mmol/L-NG) and high glucose (25 mmol/L-HG) conditions. 3H-proline incorporation in cardiac fibroblasts was also assessed as a marker of collagen synthesis. The role of p300 activity in modifying TGF-? activity was investigated with a known p300 inhibitor, curcumin or p300 siRNA in vitro, and the functional effects of p300 inhibition were assessed using curcumin in a hemodynamically validated model of diabetic cardiomyopathy - the diabetic TG m(Ren-2)27 rat.ResultsIn vitro, H9c2 cells exposed to HG demonstrated increased p300 activity, Smad2 acetylation and increased TGF-? activity as assessed by Smad7 induction (all p <?0.05 c/w NG). Furthermore, HG induced 3H-proline incorporation as a marker of collagen synthesis (p <?0.05 c/w NG). p300 inhibition, using either siRNA or curcumin reduced p300 activity, Smad acetylation and TGF-? activity (all p <?0.05 c/w vehicle or scrambled siRNA). Furthermore, curcumin therapy reduced 3H-proline incorporation in HG and TGF-? stimulated fibroblasts (p <?0.05 c/w NG). To determine the functional significance of p300 inhibition, diabetic Ren-2 rats were randomized to receive curcumin or vehicle for 6 weeks. Curcumin treatment reduced cardiac hypertrophy, improved diastolic function and reduced extracellular matrix production, without affecting glycemic control, along with a reduction in TGF-? activity as assessed by Smad7 activation (all p <?0.05 c/w vehicle treated diabetic animals).ConclusionsThese findings suggest that high glucose increases the activity of the transcriptional co-regulator p300, which increases TGF-? activity via Smad2 acetylation. Modulation of p300 may be a novel strategy to treat diabetes induced heart failure.

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Quantitative control of adaptive cardiac hypertrophy by acetyltransferase p300.

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Quantitative control of adaptive cardiac hypertrophy by acetyltransferase p300.

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