Histone deacetylase (HDAC) inhibitors attenuate cardiac hypertrophy by suppressing autophagy

Dian J Cao, Zhao Wang, Pavan K. Battiprolu, Nan Jiang, Cyndi R. Morales, Yongli Kong, Beverly A Rothermel, Thomas G. Gillette, Joseph A Hill

Research output: Contribution to journalArticle

251 Scopus citations

Abstract

Histone deacetylases (HDACs) regulate cardiac plasticity; however, their molecular targets are unknown. As autophagy contributes to pathological cardiac remodeling, we hypothesized that HDAC inhibitors target autophagy. The prototypical HDAC inhibitor (HDACi), trichostatin A (TSA), attenuated both load- and agonistinduced hypertrophic growth and abolished the associated activation of autophagy. Phenylephrine (PE)-triggered hypertrophy and autophagy in cultured cardiomyocyteswere each blocked by a panel of structurally distinct HDAC inhibitors. RNAi-mediated knockdown of either Atg5 or Beclin 1, two essential autophagy effectors, was similarly capable of suppressing ligand-induced autophagy and myocyte growth. RNAi experiments uncovered the class I isoforms HDAC1 and HDAC2 as required for the autophagic response. To test the functional requirement of autophagic activation, we studied mice that overexpress Beclin 1 in cardiomyocytes. In these animals with a fourfold amplified autophagic response to TAC, TSA abolished TAC-induced increases in autophagy and blunted load-induced hypertrophy. Finally, we subjected animals with preexisting hypertrophy to HDACi, finding that ventricular mass reverted to nearnormal levels and ventricular function normalized completely. Together, these data implicate autophagy as an obligatory element in pathological cardiac remodeling and point to HDAC1/2 as required effectors. Also, these data reveal autophagy as a previously unknown target of HDAC inhibitor therapy.

Original languageEnglish (US)
Pages (from-to)4123-4128
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number10
DOIs
StatePublished - Mar 8 2011

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