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Reversal of pathological cardiac hypertrophy via the MEF2-coregulator interface
Jianqin Wei1, Shaurya Joshi2, Svetlana Speransky1
1Department of Medicine.
Insights
Blocking MEF2 acetylation prevents and reverses cardiac hypertrophy, a response to hemodynamic stress. This targeted approach normalizes heart structure and function without impairing physiologic adaptation.
Area of Science:
- Cardiology
- Molecular Biology
- Biochemistry
Background:
- Cardiac hypertrophy, a response to hemodynamic stress, is linked to cardiac dysfunction and mortality.
- The precise pathological nature of hypertrophy remains under investigation.
- Myocardial gene expression changes driving hypertrophy involve MEF2 transcription factors and p300.
Purpose of the Study:
- To investigate the role of MEF2 acetylation in cardiac adaptation to stress.
- To determine the effects of inhibiting MEF2 acetylation on pathological cardiac hypertrophy.
Main Methods:
- Utilized genetic (nonacetylatable MEF2 mutants) and small-molecule (8MI) probes.
- Assessed hypertrophy in cultured cardiac myocytes and in vivo stress models.
- Analyzed MEF2 acetylation, HDAC4/5 nuclear export, p300 induction, and gene expression changes.
Main Results:
- Nonacetylatable MEF2 mutants and 8MI prevented hypertrophy in vitro.
- 8MI inhibited cardiac hypertrophy in three stress models and reversed established hypertrophy in vivo.
- 8MI normalized myocardial structure and function, with reversible effects that did not impair training adaptation.
- Mechanistically, 8MI blocked stress-induced MEF2 acetylation, HDAC4/5 nuclear export, and p300 induction, while normalizing gene expression dysregulated by stress.
Conclusions:
- MEF2 acetylation is essential for the development and maintenance of pathological cardiac hypertrophy.
- Inhibiting MEF2 acetylation offers a therapeutic strategy for reversing hypertrophy and restoring cardiac function.
- This approach allows recovery from pathological hypertrophy without compromising beneficial physiologic adaptations.
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.
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