Sirtuins (
SIRT) exhibit deacetylation or
ADP-ribosyltransferase activity and regulate a wide range of cellular processes in the nucleus, mitochondria, and cytoplasm. The role of the only
sirtuin that resides in the cytoplasm,
SIRT2, in the development of ischemic injury and
cardiac hypertrophy is not known. In this paper, we show that the hearts of mice with deletion of
Sirt2 (
Sirt2-/-) display improved cardiac function after
ischemia-reperfusion (I/R) and pressure overload (PO), suggesting that
SIRT2 exerts maladaptive effects in the heart in response to stress. Similar results were obtained in mice with cardiomyocyte-specific
Sirt2 deletion. Mechanistic studies suggest that
SIRT2 modulates cellular levels and activity of nuclear factor (erythroid-derived 2)-like 2 (NRF2), which results in reduced expression of
antioxidant proteins. Deletion of Nrf2 in the hearts of
Sirt2-/- mice reversed protection after PO. Finally, treatment of mouse hearts with a specific
SIRT2 inhibitor reduced cardiac size and attenuates
cardiac hypertrophy in response to PO. These data indicate that
SIRT2 has detrimental effects in the heart and plays a role in cardiac response to injury and the progression of
cardiac hypertrophy, which makes this
protein a unique member of the
SIRT family. Additionally, our studies provide a novel approach for treatment of
cardiac hypertrophy and injury by targeting
SIRT2 pharmacologically, providing a novel avenue for the treatment of these disorders.