Abstract Body: Background
Class IIa histone deacetylases (HDACs) are composed of 4 members: HDAC4, HDAC5, HDAC7 and HDAC9. HDAC4, HDAC5 and HDAC9 are expressed in adult cardiomyocytes (CMs) and have been shown to protect against pathologic cardiac hypertrophy. In contrast, HDAC7 is not expressed in adult CMs. Thus, it is unclear the potential function of HDAC7 under hypertrophic stresses and its underlying mechanisms for potential therapeutic applications.

Methods
Through molecular, biochemical and physiological studies in vitro and in vivo, we tested whether overexpression of HDAC7 protects against pathologic cardiac hypertrophy.

Results
We found that Hdac7 overexpression in cultured neonatal mouse CMs significantly mitigated hypertrophic response induced by Angiotensin II treatment: reduced cell size increase and blunted hypertrophic gene upregulation (i.e., ANF, BNP, Myh7). Further, Hdac7 overexpression in adult hearts significantly alleviated hypertrophic responses elicited through transverse aortic constriction such as cardiac enlargement, declined cardiac function, and hypertrophic gene upregulation. Mechanistically, we found that HDAC7 suppresses hypertrophic programs by interacting with and repressing myocyte enhancer factor 2D (MEF2D), a major pro-hypertrophic transcription factor, which otherwise induced pro-hypertrophic gene expression (i.e., ACTC1, Tnni3, Myl2 etc). In contrast, overexpression of an mutated HDAC7 (HDACL112A) that abolishes its binding capacity with MEF2, fails to protect against hypertrophy.

Conclusion
Our findings revealed that HDAC7 protects against pathologic cardiac hypertrophy by interacting with and repressing MEF2D expression, uncovering a potential new therapeutic strategy.