Epigenetic dysregulation plays a crucial role in cardiovascular diseases. Previously， we reported that acetyltransferase p300 (ATp300) inhibitor L002 prevents hypertension-induced cardiac hypertrophy and fibrosis in a murine model. In this short communication， we show that treatment of hypertensive mice with ATp300-specific small molecule inhibitor L002 or C646 reverses hypertension-induced left ventricular hypertrophy， cardiac fibrosis and diastolic dysfunction， without reducing elevated blood pressures. Biochemically， treatment with L002 and C646 also reverse hypertension-induced histone acetylation and myofibroblast differentiation in murine ventricles. Our results confirm and extend the role of ATp300， a major epigenetic regulator， in the pathobiology of cardiac hypertrophy and fibrosis. Most importantly， we identify the efficacies of ATp300 inhibitors C646 and L002 in reversing hypertension-induced cardiac hypertrophy and fibrosis， and discover new anti-hypertrophic and anti-fibrotic candidates.