Myocardin-related transcription factor-A (MRTF-A) is a remarkably potent transcriptional co activator expressed in a broad range of embryonic and adult tissues. It shows that MRTF-A might induce cardiac hypertrophy in our previous studys. However, it remains poorly understood about the effects of MRTF-A in cardiac hypertrophy. Here, we show that the p300, a his tone acetyltransferase, enhanced transcriptional activity of MRTF-A. Conversely, class II his tone deacetylases HDAC5 suppress cardiac-special genes activation by MRTF-A and p300. These findings point that MRTF-A maybe a nexus for regulation of cardiac hypertrophic-special genes expression by changes in chromatin acetylation. Our results provide novel evidence to explore the roles of MRTFs and their co-factors in cardiac hypertrophy for the future studies.