In this study, we show that Sirt5 KO attenuates TAC-induced cardiac hypertrophy and improves cardiac function in mice, which is associated with higher AMP/ATP ratio and AMPK activation, confirming the heart-protective role of AMPK activation in a mouse model of pressure overload-induced left ventricular hypertrophy. This evidence concerns the gene PRKAA2 and cardiac hypertrophy.