Diverse cardiac diseases are known to induce cardiac hypertrophy, which often ends up in disastrous dilatation and heart failure. We have previously reported that cardiac hypertrophy could be blocked by class I histone deacetylase (HDAC) inhibitor, which prompted us to investigate the regulatory mechanism of class I HDAC in cardiac hypertrophy. Cardiac hypertrophy-inducing stimuli such as aortic banding, isoproterenol (ISP), or angiotensin II-infusion elevated the enzymatic activity of nuclear HDAC2, one of class I HDACs. Among possible regulatory mechanisms, we ruled out alterations in protein amount, intracellular localization or phosphorylation level of HDAC2. Hypertrophic stimuli induced expression of heat shock protein (HSP) 72. Both HSP56 and HSP72 increased HDAC2 activity but only HSP72 interacted with HDAC2. Heat shock to cardiomyocytes or mice activated HDAC2 and atrial natriuretic factor promoter. Repeated heat shock induced cardiac hypertrophy in mice. In HSP72 null mice, ISP infusion failed to increase both HDAC2 activity and heart weight. These results suggest that induction of chaperones in response to various stimuli and ensuing activation of HDAC2 mediate cardiac hypertrophy, and provide clue on how heart diseases such as myocardial infarction known to induce HSP cause cardiac hypertrophy.