Activation of histone deacetylase 2 by inducible heat shock protein 70 in cardiac hypertrophy.
Diverse cardiac diseases induce cardiac hypertrophy, which leads to dilatation and heart failure. We previously reported that hypertrophy can be blocked by class I histone deacetylase (HDAC) inhibitor, which prompted us to investigate the regulatory mechanism of class I HDACs. Cardiac hypertrophy was introduced by aortic banding, by infusion of isoproterenol or angiotensin II, or by swimming. Hypertrophic stimuli transiently elevated the activity of histone deacetylase-2 (Hdac2), a class I HDAC. In cardiomyocytes, forced expression of Hdac2 simulated hypertrophy in an Akt-dependent manner, whereas enzymatically inert Hdac2 H141A failed to do so. Hypertrophic stimuli induced the expression of heat shock protein (Hsp)70. The induced Hsp70 physically associated with and activated Hdac2. Hsp70 overexpression produced a hypertrophic phenotype, which was blocked either by siHdac2 or by a dominant negative Hsp70DeltaABD. In Hsp70.1(-/-) mice, cardiac hypertrophy and Hdac2 activation were significantly blunted. Heat shock either to cardiomyocytes or to mice activated Hdac2 and induced hypertrophy. However, heat shock-induced Hdac2 activation was blunted in the cardiomyocytes isolated from Hsp70.1(-/-) mice. These results suggest that the induction of Hsp70 in response to diverse hypertrophic stresses and the ensuing activation of HDAC2 trigger cardiac hypertrophy, emphasizing HSP70/HDAC2 as a novel mechanism regulating hypertrophy.
Kee
Hae Jin
HJ
Department of Pharmacology, Chonnam National University Medical School, Gwangju, South Korea.
Eom
Gwang Hyeon
GH
Joung
Hosouk
H
Shin
Sera
S
Kim
Ju-Ryoung
JR
Cho
Young Kuk
YK
Choe
Nakwon
N
Sim
Bo-Woong
BW
Jo
Daewoong
D
Jeong
Myung Ho
MH
Kim
Kyung Keun
KK
Seo
Jeong-Sun
JS
Kook
Hyun
H
D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology*; D004452:Echocardiography; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D050884:HSP72 Heat-Shock Proteins / Q000172:deficiency; D018869:Heat-Shock Response / Q000502:physiology*; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000473:pathology; D051381:Rats; D012097:Repressor Proteins / Q000378:metabolism*; D014162:Transfection
D050884:HSP72 Heat-Shock Proteins; D012097:Repressor Proteins; C533424:Hdac2 protein, mouse; C533426:Hdac2 protein, rat; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases