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Reversal of pathological cardiac hypertrophy via the MEF2-coregulator interface
Jianqin Wei, … , Lin Chen, Nanette H. Bishopric
Jianqin Wei, … , Lin Chen, Nanette H. Bishopric
Published September 7, 2017
Citation Information: JCI Insight. 2017;2(17):e91068. https://doi.org/10.1172/jci.insight.91068.
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Research Article Cardiology Cell biology

Reversal of pathological cardiac hypertrophy via the MEF2-coregulator interface

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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.

Authors

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

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Figure 5

8MI decreases stress-induced muscle enhancer factor-2 (MEF2) acetylation.

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8MI decreases stress-induced muscle enhancer factor-2 (MEF2) acetylation...
(A) Acetyl-Mef2 (Ac-Mef2) levels in nonstressed murine hearts with and without 8MI. Mice were administered 8MI 40 mg/kg or its vehicle (DMSO) by i.p. injection for 4 weeks. Myocardial lysates were immunoprecipitated with anti–acetyl-lysine (anti–Ac-Lys) antibody and immunoblotted with antibodies against total Ac-Lys or MEF2. Ponceau S stain was used to confirm loading. Left: Representative Western blots. Right: Quantification. Graph displays full data range with mean. Open bars: Total Ac-Lys. Filled bars: Ac-Mef2. n = 3 per treatment group. (B and C) Mef2 acetylation is increased by transverse aortic coarctation (TAC) and reduced by 8MI. Mice were subjected to TAC or a sham operation, as described in Methods. Myocardial lysates were immunoprecipitated with (B) anti–pan-Mef2 and -Gata4 antibodies, or (C) anti–Ac-Lys antibody and probed with antibodies against Mef2, Gata4, or Ac-Lys as shown. (D) Quantification of data as in C normalized to total Ac-Lys. Dark bars: Ac-Mef2. Light bars: Ac-Gata4. Graph displays full data range with mean. n = at least 3 biological replicates; exact P values are indicated (2-way ANOVA with post-hoc testing for multiple comparisons). n.s., not significant; n.a.u., normalized arbitrary units.

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