SIRT1 enhances endothelium-dependent relaxation through an eNOS-independent mechanism

Abstract

SIRT1 is a class III NAD+-dependent deacetylase which involved in a wide range of cellular processes and possesses vascular protective effects. SIRT1 maintains vascular homeostasis by reducing endothelial activation, preventing endothelial senescence, and promoting endothelium-dependent relaxations of vascular smooth muscle. To elucidate the molecular mechanisms underlying the SIRT1-mediated vascular protection, an endothelium-specific SIRT1 transgenic mouse model was engineered. The vascular responsiveness of the thoracic aorta was determined using a Mulvany-Halpern wire myograph for the recording of isometric force. The results showed that selective over-expression of SIRT1 in endothelial cells significantly enhanced acetylcholine-evoked aortic relaxation in mice of different ages [8, 12, 16 and 20 weeks] and prevented high fat diet-induced endothelial dysfunction. The enhanced endothelium-dependent relaxation in the aorta of these SIRT1 transgenic mice persisted in the presence of L-NAME, an inhibitor of NO synthesis. Moreover, the eNOS activity was not significantly different from that in preparations of wild type mice. These findings suggest that an eNOS/NO independent mechanism is involved in the vascular regulation by SIRT1.