Abstract 18465: p300 Regulates Cardiac Myocyte Growth Through MIR374–5p and MIR142–5p
Background: Acetyltransferase p300 is a dose-dependent and limiting regulator of cardiac hypertrophy. The downstream targets of p300 are incompletely characterized.
Hypothesis: p300 regulates hypertrophy by controlling expression of specific microRNAs.
Methods and Results: Transcription analysis revealed significant down-regulation of microRNAs miR374–5p (374) and miR142–3p and -5p (142) in 1 month old p300 transgenic mouse left ventricles vs. wt littermates. Induction of p300 was associated with downregulation of miR374 and miR142 in both fetal bovine serum (FBS)-induced hypertrophy of neonatal rat myocytes (NRVM) in culture and following transverse aortic coarctation in vivo. Adenovirus-mediated overexpression of p300 in NRVM caused robust downregulation of both miR374 and miR142. Conversely, siRNA-mediated knockdown of p300 upregulated both microRNAs, suggesting that p300 is both necessary and sufficient to drive their expression. NRVM were then transfected with lentiviral vectors expressing miR374 and miR142 and stimulated with FBS. Strikingly, miR374–5p completely blocked the hypertrophic response to FBS. Gain and loss of expression of miR374 was associated with parallel changes in EGR4, a growth-associated transcriptional repressor. At the same time, gain and loss of miR374 expression caused reciprocal changes in HMGB2, a transcriptional activator upregulated in several types of cardiomyopathy. Overexpression of miR142 did not affect cell size, but strongly downregulated alpha-actinin and cardiac troponin T. Other sarcomeric isoforms, including Tni2, Tnt2, Myh3 and Mlc1, were regulated in parallel with miR142 loss and gain.
Conclusion: We propose that p300 promotes hypertrophy in part by downregulating miR374–5p and miR142–5p, relieving a repression of transcription factors involved in the early growth response and promoting specific alterations in sarcomeric protein content.
- © 2010 by American Heart Association, Inc.