Quantitative Control of Adaptive Cardiac Hypertrophy by Acetyltransferase p300

Abstract

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.

Kruppel-like Factor 15 Is a Critical Regulator of Cardiac Lipid Metabolism

“…Previous studies have implicated p300 acetyltransferase as a positive regulator of pathologic cardiomyocyte hypertrophy, possibly via its ability to acetylate prohypertrophic transcription factors, such as GATA4, MEF2, and p53 (21,(47)(48)(49)(50). Prior work from our group has shown that Klf15 expression is dramatically reduced during pathologic cardiac hypertrophy, an event that releases repression of GATA4, MEF2, and the p300-p53 transcriptional module (20,21).…”

Role of Apoptosis Signal-regulating Kinase 1 (ASK1) as an Activator of the GAPDH-Siah1 Stress-Signaling Cascade

“…It is known that p300 has multiple functions in different conditions: for example, in the heart p300 activation can lead to heart hypertrophy mediated by myocyte enhancer factor-2 (MEF2) (48), whereas in the brain p300 affects memory function via cAMP response element-binding (CREB) (49). Roles for stressors in these conditions are appreciated, but further molecular mechanisms remain to be elucidated.…”

Resveratrol Improves Cardiomyopathy in Dystrophin-deficient Mice through SIRT1 Protein-mediated Modulation of p300 Protein*

“…We found elevated p300 protein levels in mdx heart tissues. High p300 levels are found in the failing heart in humans and mice (4), and combination studies using cardiac p300 transgenic mice and p300 heterozygous knock-out mice showed that mortality and cardiac mass are directly regulated by myocardial p300 protein levels (4). Because a 1.5-3.7-fold overexpression of p300 causes prominent cardiac hypertrophy in p300-transgenic mice (4), the 2.8-fold increase in p300 protein level in the mdx heart is sufficient to induce cardiac hypertrophy.…”

“…Although p300 is essential for cardiac development (3), it also plays a key role in cardiac hypertrophy and heart failure by acetylating and activating myocyte enhancer factor-2 (4) and GATA4 (5) transcription factors. The dose of p300 seems to be critical for development of cardiac hypertrophy, because overexpression of p300 induces cardiomyocyte hypertrophy in vitro and in vivo, whereas down-regulating p300 ameliorated cardiomyopathy (4). In addition, cardiac fibrosis impairs myocardial diastolic function in hypertrophied and failing hearts, and p300 promotes tissue fibrosis by binding to and activating Smad3 (6).…”