Inhibition of histone deacetylation blocks cardiac hypertrophy induced by angiotensin II infusion and aortic banding

Hae Jin Kee, Il Suk Sohn, Kwang Il Nam, Jong Eun Park, Yong Ri Qian, Zhan Yin, Youngkeun Ahn, Myung Ho Jeong, Yung Jue Bang, Nacksung Kim, Jong Keun Kim, Kyung Keun Kim, Jonathan A. Epstein, Hyun Kook

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237 Scopus citations

Abstract

BACKGROUND-: A number of distinct stress signaling pathways in myocardium cause cardiac hypertrophy and heart failure. Class II histone deacetylases (HDACs) antagonize several stress-induced pathways and hypertrophy. However, cardiac hypertrophy induced by transgenic overexpression of the homeodomain only protein, HOP, can be prevented by the nonspecific HDAC inhibitors trichostatin A and valproic acid, suggesting that alternate targets that oppose class II HDAC function might exist in myocardium. We tested the effects of several HDAC inhibitors, including a class I HDAC-selective inhibitor, SK-7041, on cardiac hypertrophy induced by angiotensin II (Ang II) treatment or aortic banding (AB). METHODS AND RESULTS-: Cardiac hypertrophy was induced by chronic infusion of Ang II or by AB in mice or rats and evaluated by determining the ratio of heart weight to body weight or to tibia length, cross-sectional area, or echocardiogram. Cardiac hypertrophy induced by Ang II or AB for 2 weeks was significantly reduced by simultaneous administration of trichostatin A, valproic acid, or SK-7041. Echocardiogram revealed that exaggerated left ventricular systolic dimensions were relieved by HDAC inhibitors. HDAC inhibitors partially reversed preestablished cardiac hypertrophy and improved survival of AB mice. The expressions of atrial natriuretic factor, α-tubulin, β-myosin heavy chain, and interstitial fibrosis were reduced by HDAC inhibition. CONCLUSIONS-: These results suggest that the predominant effect of HDAC inhibition, mainly mediated by class I HDACs, is to prevent cardiac hypertrophy in response to a broad range of agonist and stretch stimuli.

Original languageEnglish
Pages (from-to)51-59
Number of pages9
JournalCirculation
Volume113
Issue number1
DOIs
StatePublished - 1 Jan 2006

Keywords

  • Angiotensin
  • Aortic banding
  • Histone deacetylases
  • Hypertrophy

Cite this

Kee, H. J., Sohn, I. S., Nam, K. I., Park, J. E., Qian, Y. R., Yin, Z., Ahn, Y., Jeong, M. H., Bang, Y. J., Kim, N., Kim, J. K., Kim, K. K., Epstein, J. A., & Kook, H. (2006). Inhibition of histone deacetylation blocks cardiac hypertrophy induced by angiotensin II infusion and aortic banding. Circulation, 113(1), 51-59. https://doi.org/10.1161/CIRCULATIONAHA.105.559724