Abstract
ObjectiveTo characterize downstream effectors of p300 acetyltransferase in the myocardium.BackgroundAcetyltransferase p300 is a central driver of the hypertrophic response to increased workload, but its biological targets and downstream effectors are incompletely known.Methods and ResultsMice expressing a myocyte-restricted transgene encoding acetyltransferase p300, previously shown to develop spontaneous hypertrophy, were observed to undergo robust compensatory blood vessel growth together with increased angiogenic gene expression. Chromatin immunoprecipitation demonstrated binding of p300 to the enhancers of the angiogenic regulators Angpt1 and Egln3. Interestingly, p300 overexpression in vivo was also associated with relative upregulation of several members of the anti-angiogenic miR-17∼92 cluster in vivo. Confirming this finding, both miR-17-3p and miR-20a were upregulated in neonatal rat ventricular myocytes following adenoviral transduction of p300. Relative expression of most members of the 17∼92 cluster was similar in all 4 cardiac chambers and in other organs, however, significant downregulation of miR-17-3p and miR-20a occurred between 1 and 8 months of age in both wt and tg mice. The decline in expression of these microRNAs was associated with increased expression of VEGFA, a validated miR-20a target. In addition, miR-20a was demonstrated to directly repress p300 expression through a consensus binding site in the p300 3′UTR. In vivo transduction of p300 resulted in repression both of p300 and of p300-induced angiogenic transcripts.Conclusionp300 drives an angiogenic transcription program during hypertrophy that is fine-tuned in part through direct repression of p300 by miR-20a.
Highlights
In the normal heart, myocardial mass, vascular density and workload are closely balanced [1,2,3,4]
Hypertrophy appears to be associated with a specific defect in compensatory angiogenesis despite the presence of tissue hypoxia [9] and this deficit has been directly implicated in the conversion of compensatory to pathological hypertrophy in animal models, associated with impaired expression of angiogenic factors such as HIF-1a, HIF-2a and VEGFR2 [7,9,10,11,12]
Heterozygous deletion of p300 impairs the development of hypertrophy in response to pressure overload, while modest (2x) myocardial overexpression of p300 reproduces molecular and histopathologic phenomena associated with early, adaptive hypertrophy [13]
Summary
Mice expressing a myocyte-restricted transgene encoding acetyltransferase p300, previously shown to develop spontaneous hypertrophy, were observed to undergo robust compensatory blood vessel growth together with increased angiogenic gene expression. P300 overexpression in vivo was associated with relative upregulation of several members of the anti-angiogenic miR-17,92 cluster in vivo. Confirming this finding, both miR-17-3p and miR-20a were upregulated in neonatal rat ventricular myocytes following adenoviral transduction of p300. MiR-20a was demonstrated to directly repress p300 expression through a consensus binding site in the p300 39UTR. Conclusion: p300 drives an angiogenic transcription program during hypertrophy that is fine-tuned in part through direct repression of p300 by miR-20a
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