Histone Deacetylase 7 protects against pathologic cardiac hypertrophy

Pathological cardiac hypertrophy is a major precursor to heart failure, yet the transcriptional mechanisms that restrain maladaptive remodeling remain incompletely defined. Class IIa histone deacetylases (HDAC4, HDAC5, and HDAC9) modulate cardiac hypertrophy but exhibit paradoxical effects, underscoring the need for more precise therapeutic targets. Unlike other Class IIa HDACs, HDAC7 is not expressed in adult cardiomyocytes (CMs), and its role in cardiac stress responses is unknown.

We used molecular, biochemical, and physiological approaches in vitro and in vivo to determine whether HDAC7 overexpression protects against pathological cardiac hypertrophy.

HDAC7 overexpression attenuated angiotensin II-induced cardiomyocyte enlargement and reduced hypertrophic gene expression (ANF, BNP, βMHC) in neonatal mouse and human induced pluripotent stem cell-derived CMs. In vivo, HDAC7 markedly reduced transverse aortic constriction-induced cardiac hypertrophy, fibrosis, and functional decline, while preventing stress-induced transcriptional reprogramming. Mechanistically, HDAC7 directly interacts with the pro-hypertrophic transcription factor MEF2D and represses its target genes (Actc1, Tnni3, Myl2). A MEF2-binding-deficient HDAC7 mutant (HDAC7-L112A) failed to confer protection, demonstrating that MEF2 repression is essential for HDAC7-mediated effects.

HDAC7 is a distinct Class IIa HDAC that suppresses pathological cardiac remodeling via a HDAC7-MEF2D axis, highlighting a potential epigenetic strategy to prevent heart failure progression.