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.

Automated summary

Atherosclerosis is linked to endothelial dysfunction and vascular inflammation, and SIRT3 and NAD(+) play critical roles in maintaining normal mitochondrial function and improving endothelial function. The deletion of SIRT3 in endothelial cells accelerates atherosclerosis and amplifies vascular inflammation and oxidative stress. Treatment with NAD(+) attenuates these effects. The study also shows that NAD(+) supplementation improves endothelial function and reduces plaque formation in mouse models of atherosclerosis.