SIRT3 Deficiency Induces Endothelial Insulin Resistance and Blunts Endothelial-Dependent Vasorelaxation in Mice and Human with Obesity

Abstract

Recent evidence implicates the critical role of Sirtuin 3 (SIRT3) in the development of many metabolic diseases, but the contribution of SIRT3 to vascular homeostasis remains largely unknown. The aim of this study was to investigate the role of SIRT3 in endothelial insulin resistance and vascular dysfunction in obesity. We found an impaired insulin-induced mesenteric vasorelaxation and concomitant reduced vascular SIRT3 expression in morbid obese human subjects compared with the non-obese subjects. Downregulation of SIRT3 in cultured human endothelial cells increased mitochondrial reactive oxygen species (mtROS) and impaired insulin signaling as evidenced by decreased phosphorylation of Akt and endothelial nitric oxide synthase and subsequent reduced nitric oxide (NO) release. In addition, obese mice induced by 24-week high-fat diet (HFD) displayed an impaired endothelium-dependent vasorelaxation to both insulin and acetylcholine, which was further exacerbated by the gene deletion of Sirt3. Scavenging of mtROS not only restored insulin-stimulated NO production in SIRT3 knockdown cells, but also improved insulin-induced vasorelaxation in SIRT3 knockout mice fed with HFD. Taken together, our findings suggest that SIRT3 positively regulates endothelial insulin sensitivity and show that SIRT3 deficiency and resultant increased mtROS contribute to vascular dysfunction in obesity.

α-Linolenic acid but not linolenic acid protects against hypertension: critical role of SIRT3 and autophagic flux

“…Previous data from other labs as well as ours have shown that SIRT3 deficiency and resultant SOD2 hyperacetylation and mitochondrial ROS overproduction contribute to the development of hypertension and vascular dysfunction in obesity 10,18 . On the other hand, ALA has been reported to have an anti-oxidative property.…”

Metformin in contrast to berberine reversed arsenic‐induced oxidative stress in mitochondria from rat pancreas probably via Sirt3‐dependent pathway

“…Conversely, Sirt3 affects mitochondrial enzymatic pathways including Krebs cycle and succinate dehydrogenase in which by binding and deacetylating the later, improves its activity . Also, Sirt3, a mitochondrial enzyme that has been shown to regulate insulin secretion and its downregulation connected to diminution of insulin sensitivity . From our data and at the presence of ATO, insulin resistance and Sirt3 levels were found to be fairly elevated that could be the result of succinate dehydrogenase decline (Figure G) and suggests a compensating mechanism that elevations of Sirt3 support it (Figure H).…”

Sirtuin 3 Deficiency Accelerates Hypertensive Cardiac Remodeling by Impairing Angiogenesis

“…37 Although mitochondrial content in endothelial cells is modest compared with other cell types, SIRT3 exerts protective effects in response to various damage factors involved in endothelial dysfunction, such as Ang II, transforming growth factor-b, and high glucose. [38][39][40] Therefore, we conclude that the reduced microvascular formation and VEGF expression in cardiac tissue was accompanied by a loss of mitochondrial SIRT3 during Ang II-induced cardiac remodeling. In parallel, SIRT3 depletion reveals no compensatory effect existing from other mitochondrial Sirtuins (SIRT4 and SIRT 5) (data not shown).…”

“…Mitochondrial SIRT3 is highly expressed in metabolically active tissues, such as the heart, liver, kidney, and brown adipose tissue . Although mitochondrial content in endothelial cells is modest compared with other cell types, SIRT3 exerts protective effects in response to various damage factors involved in endothelial dysfunction, such as Ang II, transforming growth factor‐β, and high glucose . Therefore, we conclude that the reduced microvascular formation and VEGF expression in cardiac tissue was accompanied by a loss of mitochondrial SIRT3 during Ang II–induced cardiac remodeling.…”