Sirtuin 3 Dependent and Independent Effects of NAD(+) to Suppress Vascular Inflammation and Improve Endothelial Function in Mice

Atherosclerosis is initiated by endothelial cell dysfunction and vascular inflammation under the condition of hyperlipidemia. Sirtuin 3 (SIRT3) is a nicotinamide adenine dinucleotide (NAD(+))-dependent mitochondrial deacetylase, which plays a key role in maintaining normal mitochondrial function. The present study tested whether endothelial-selective SIRT3 deletion accelerates vascular inflammation and oxidative stress, and assessed the protective effect of NAD(+) to alleviate these changes in endothelial cells and in mouse models of atherosclerosis. We found that the selective deletion of SIRT3 in endothelial cells further impaired endothelium-dependent vasodilatation in the aorta treated with IL-1 beta, which was accompanied by upregulation of vascular inflammation markers and mitochondrial superoxide overproduction. Excepting the dysfunction of endothelium-dependent vasodilatation, such effects could be attenuated by treatment with NAD(+). In human umbilical vein endothelial cells, SIRT3 silencing potentiated the induction of inflammatory factors by IL-1 beta, including VCAM-1, ICAM-1, and MCP1, and the impairment of mitochondrial respiration, both of which were alleviated by NAD(+) treatment. In ApoE-deficient mice fed with a high-cholesterol diet, supplementation with nicotinamide riboside, the NAD(+) precursor, reduced plaque formation, improved vascular function, and diminished vascular inflammation. Our results support the SIRT3-dependent and -independent of NAD(+) to improve endothelial function in atherosclerosis.