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Sirtuin 3 (Sirt3) is an NAD + -dependent mitochondrial deacetylase associated with superoxide dismutase 2 (SOD2)-mediated protection from oxidative stress. We have reported accelerated weight gain and impaired metabolic flexibility in atherosclerotic  Sirt3  − / −  mice. Oxidative stress is a hallmark of endothelial dysfunction. Yet, the role of Sirt3 in this context remains unknown. Thus, we aimed to unravel the effects of endogenous Sirt3 on endothelial function and oxidative stress. Knockdown of Sirt3 in human aortic endothelial cells (HAEC) increased intracellular mitochondrial superoxide accumulation, as assessed by electron spin resonance spectroscopy and fluorescence imaging. Endothelium-dependent relaxation of aortic rings from  Sirt3  − / −  mice exposed to a normal diet did not differ from  wild - type  controls. However, following 12 weeks of high-cholesterol diet and increasing oxidative stress, endothelial function of  Sirt3  − / −  mice was mildly impaired compared with  wild - type  controls. Relaxation was restored upon enhanced superoxide scavenging using pegylated superoxide dismutase. Knockdown of  Sirt3  in cultured HAEC diminished SOD2 specific activity, which was compensated for by a CCAAT/enhancer binding protein beta (C/EBP-β)-dependent transcriptional induction of SOD2. Abrogation of this feedback regulation by simultaneous knockdown of  C/EBP - β  and  Sirt3  exacerbated mitochondrial superoxide accumulation and culminated into endothelial cell death upon prolonged culture. Taken together,  Sirt3  deficiency induces a mild, superoxide-dependent endothelial dysfunction in mice fed a high-cholesterol diet. In cultured endothelial cells, a novel C/EBP-β-dependent rescue mechanism maintains net SOD2 activity upon transient knockdown of  Sirt3 .   Electronic supplementary material  The online version of this article (doi:10.1007/s00395-016-0552-7) contains supplementary material, which is available to authorized users.

basic research in cardiology

Mild endothelial dysfunction in Sirt3 knockout mice fed a high-cholesterol diet: protective role of a novel C/EBP-β-dependent feedback regulation of SOD2