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


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, alpha-tubulin, beta-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.
Kee
Hae Jin
HJ
Department of Pharmacology, Research Institute of Medical Sciences and Medical Research Center for Gene Regulation, Chonnam National University Medical School, Gwangju, South Korea.
Sohn
Il Suk
IS
Nam
Kwang Il
KI
Park
Jong Eun
JE
Qian
Yong Ri
YR
Yin
Zhan
Z
Ahn
Youngkeun
Y
Jeong
Myung Ho
MH
Bang
Yung-Jue
YJ
Kim
Nacksung
N
Kim
Jong-Keun
JK
Kim
Kyung Keun
KK
Epstein
Jonathan A
JA
Kook
Hyun
H
D000804:Angiotensin II / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001024:Aortic Valve Stenosis / Q000150:complications*; D015415:Biomarkers / Q000032:analysis; D006332:Cardiomegaly / Q000139:chemically induced* / Q000188:drug therapy* / Q000517:prevention & control; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D056572:Histone Deacetylase Inhibitors; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome
D015415:Biomarkers; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D000804:Angiotensin II