In this study, we demonstrated that (1) overexpression of PRMT5 in cardiomyocytes accelerates cardiac hypertrophy and LV dysfunction in mice undergoing TAC surgery, (2) EPZ015666, a selective PRMT5 inhibitor, or PRMT5 knockdown abrogates PE-induced cardiomyocyte hypertrophy, and (3) PRMT5 symmetrically methylates p300 at R200, enhancing its HAT activity and promoting H3K9 acetylation. The gene discussed is TMPRSS11D; the disease is cardiac hypertrophy.