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 non-specific HDAC inhibitors trichostatin A (TSA) and valproic acid (VAL), suggesting that class I HDACs might have activities in myocardium that oppose class II HDACs. We here tested the effects of non-specific HDAC inhibitors, on cardiac hypertrophy induced by angiotensin II (ANG)-treatment or aortic banding (AB). Cardiac hypertrophy was induced by chronic infusion of ANG or by AB in mice or rats. Hypertrophy was evaluated by checking the ratio of heart weight to body weight (HW/BW) or cross-sectional area. The expression of hypertrophy markers was examined. ANG and AB increased HW/BW and these increases were significantly reduced by TSA or VAL administration, as were associated broadening of cross-sectional areas of cardiomyocytes. HDAC inhibitor treatments increased acetylation of histone H4. TSA did not affect the increase in blood pressure by ANG. The expression of atrial natriuretic factor (ANF), ��-tubulin, and ��-myosin heavy chain (��-MHC) were reduced by HDAC inhibition. Type I collagen deposition and interstitial fibrosis were attenuated by TSA. These results suggest that the predominant effect of non-specific HDAC inhibition is to prevent induction of cardiac hypertrophy in response to a broad range of agonist and stretch stimuli.��