Reversal of pathological cardiac hypertrophy via the MEF2-coregulator interface

Jianqin Wei, Shaurya Joshi, Svetlana Speransky, Christopher Crowley, Nimanthi Jayathilaka, Xiao Lei, Yongqing Wu, David Gai, Sumit Jain, Michael Hoosien, Yan Gao, Lin Chen, Nanette H. Bishopric

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Cardiac hypertrophy, as a response to hemodynamic stress, is associated with cardiac dysfunction and death, but whether hypertrophy itself represents a pathological process remains unclear. Hypertrophy is driven by changes in myocardial gene expression that require the MEF2 family of DNA-binding transcription factors, as well as the nuclear lysine acetyltransferase p300. Here we used genetic and small-molecule probes to determine the effects of preventing MEF2 acetylation on cardiac adaptation to stress. Both nonacetylatable MEF2 mutants and 8MI, a molecule designed to interfere with MEF2-coregulator binding, prevented hypertrophy in cultured cardiac myocytes. 8MI prevented cardiac hypertrophy in 3 distinct stress models, and reversed established hypertrophy in vivo, associated with normalization of myocardial structure and function. The effects of 8MI were reversible, and did not prevent training effects of swimming. Mechanistically, 8MI blocked stress-induced MEF2 acetylation, nuclear export of class II histone deacetylases HDAC4 and -5, and p300 induction, without impeding HDAC4 phosphorylation. Correspondingly, 8MI transformed the transcriptional response to pressure overload, normalizing almost all 232 genes dysregulated by hemodynamic stress. We conclude that MEF2 acetylation is required for development and maintenance of pathological cardiac hypertrophy, and that blocking MEF2 acetylation can permit recovery from hypertrophy without impairing physiologic adaptation.

Original languageEnglish (US)
JournalJCI Insight
Volume2
Issue number17
DOIs
StatePublished - Sep 7 2017

Keywords

  • Cardiology
  • Cell Biology
  • Cell stress
  • Epigenetics
  • Heart failure

ASJC Scopus subject areas

  • Medicine(all)

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    Wei, J., Joshi, S., Speransky, S., Crowley, C., Jayathilaka, N., Lei, X., Wu, Y., Gai, D., Jain, S., Hoosien, M., Gao, Y., Chen, L., & Bishopric, N. H. (2017). Reversal of pathological cardiac hypertrophy via the MEF2-coregulator interface. JCI Insight, 2(17). https://doi.org/10.1172/jci.insight.91068