Our laboratory has identified a critical role for the acetyltransferase p300 in the regulation of postnatal cardiac myocyte growth. We find that acetyltransferase p300 is rapidly upregulated in most or all forms of cardiac hypertrophy. We have shown that the cellular concentration of p300 is directly and stoichometrically related to cardiac myocyte growth capacity, such that even small changes in p300 levels have large effects on myocyte growth. Loss of a single p300 allele is sufficient to impair cardiac growth with age and in response to pressure overload. We also find that p300 is also rapidly induced during ischemic and oxidative stress, where it conveys a cytoprotective signal. The rapid induction of p300 thus appears to be a critical cardiac stress response. Despite the likely importance of dynamic control of p300 levels, nothing is known about the mechanisms that control upregulation of p300 mRNA and protein levels during stress. Based on these findings, we hypothesize that (1)"immediate-early", myocyte-autonomous induction of p300 during cardiac stress is the nodal event in the induction of cardiac hypertrophy by other identified effectors, including calcineurin, and that (2) induction of p300 is mediated by a sequence of signal-responsive pre- and post- transcriptional events, including phosphorylation, acetylation, ubiquitination, and removal of repression by non-coding RNAs. We propose to test the impact of modulators of acetylation and phosphorylation, and the role of specific p300-regulated miRs, on the accumulation and acetyltransferase activity of p300 during hypertrophic signaling. We will carry out cardiac-specific deletion of p300 and CBP to determine whether these proteins have distinct or myocyte-autonomous roles in hypertrophy. Finally, we will perform genetic complementation experiments between p300tg and HDAC5- or 9-deficient mice, and between p300-deficient and calcineurin tg mice. These experiments will definitively establish the position of p300 relative to the class II histone deacetylases and calcineurin in the transduction of hypertrophic signals in vivo.
More than three million Americans are living with heart failure. Despite significant clinical advances, mortality remains extremely high;fewer than 40% will survive 5 years after their first episode of heart failure. The heart begins to undergo hypertrophy, or enlargement, months or years before it fails. Hypertrophy by itself is an independent risk factor for death. No therapy exists to prevent hypertrophy or delay its progression to heart failure. By revealing the specific molecular signals for hypertrophy, our studies may help lead to new treatments for these common and lethal forms of heart disease.
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