Stress signal to cardiomyocytes leads to maladaptive reactivation of fetal gene program and subsequent hypertrophic growth. It is well established that class II histone deacetylase (HDACs) suppresses cardiac hypertrophy and the regulatory mechanisms are under extensive investigation. Unexpectedly, we and others have found that HDAC inhibitors prevent cardiac hypertrophy induced by transgenic overexpression of homeodomain only protein or by chronic isoproterenol infusion and block fetal gene activation. However, since both class I and class II HDACs are sensitive to the inhibitors employed in those studies, it is likely that paradoxical response might be caused by class selectivity. Here we show that SK7041, a newly developed class I selective HDAC inhibitor, dramatically inhibits cardiac hypertrophy induced by aortic banding and subsequent expression of fetal cardiac genes, such as atrial natriuretic factor (ANF) and ��-myosin heavy chain (��MHC). The decrease in heart weight was accompanied with the reduction of cellular volumes. SK7041 dose-dependently increased the acetylation of histone H4 in rat neonatal cardiomyocytes. SK7041 also caused significant reduction of ANF promoter activity in both quiescent and fetal bovine serum-stimulated rat neonatal cardiomyocytes. SK-responsive element was located within the minimal promoter -638 bp region of ANF gene. However, SK7041 activated the promoter activity in 293T cells. These results suggest that class I HDAC might have opposite role to class II HDAC in the cardiomyocyte volume regulation and that certain transcription-regulatory mediator could be involved in the mechanism.