Transgenic Overexpression of Active HDAC4 in the Heart Attenuates Cardiac Function and Exacerbates Remodeling in Infarcted Myocardium

Histone deacetylases (HDACs) play a critical role in modulating cardiac function and ischemic injury. HDAC4 was found to be elevated and activated in response to injury. However, whether HDAC4 mediates cardiac function is currently unknown. In this study, we created myocyte-specific activated HDAC4 transgenic mice to examine the role of HDAC4 in mediating cardiac function during development and response to infarction. There are no differences in cardiac function and gross phenotype between wild-type and cardiomyocyte-specific HDAC4 transgenic mice at 1 mo of age. However, cardiac dysfunction and vascular growth deficiency were displayed in 6-mo-old HDAC4-transgenic mice compared with wild-type mice. Activation of HDAC4 increased heart and myocyte size, hypertrophic proteins, and interstitial fibrosis in 6-mo-old mice but not in 1-mo-old mice. To further define whether activated HDAC4 in the heart could impact myocardial function and remodeling, myocardial infarction was created in both wild-type and cardiomyocyte-specific HDAC4-transgenic mice. In myocardial infarction, the overexpression of activated HDAC4 exacerbated cardiac dysfunction and augmented cardiac remodeling and interstitial fibrosis, which was associated with the reduction of cardiokines in the heart. These results indicate the activation of HDAC4 as a crucial regulator for cardiac function in development and myocardial infarction. NEW & NOTEWORTHY We created myocyte-specific activated HDAC4-transgenic mice to examine the function of HDAC4 in mediating cardiac function. HDAC4 overexpression led to cardiac dysfunction, which was associated with increased hypertrophy and myocardial fibrosis. Furthermore, the overexpression of activated HDAC4 exacerbated cardiac dysfunction, augmented remodeling, and increased apoptosis in the infarcted heart. This is the first demonstration that transgenic overexpression of HDAC4 is crucial for modulation of cardiac function and remodeling.