Sirtuin 6 Protects Against Oxidative Stress and Vascular Dysfunction in Mice

Abstract

Objective: Sirtuin deacetylases are major regulators of organismal aging, and while depletion of sirtuin 6 (SIRT6) in mice results in a profound progeroid phenotype, the role of SIRT6 in the regulation of vasomotor function is unknown. Thus, our objective was to test the hypothesis that reductions in SIRT6 elicit endothelial dysfunction in young, genetically altered mice.Results and Approach: We used young (3 month old), littermate-matched, SIRT6 wild-type (WT), and SIRT6 heterozygous (HET) mice. SIRT6 expression (qRT-PCR) was reduced by 50% in HET mice. Carotid vessel responses to acetylcholine, sodium nitroprusside, U46619, and serotonin were examined in isolated organ chamber baths. Relaxation in response to acetylcholine (ACH) was impaired in HET mice compared to littermate-matched WT controls (67 ± 3% versus 76 ± 3%, respectively; p < 0.05), while responses to sodium nitroprusside were unchanged. Short-term incubation of carotid rings with the NAD(P)H oxidase inhibitor, apocynin, significantly improved in vessels from HET mice but not their WT littermates. Peak tension generated in response to either U46619 or serotonin was significantly blunted in HET mice compared to their WT littermates.Conclusion: These data suggest that SIRT6 is a key regulator of vasomotor function in conduit vessels. More specifically, we propose that SIRT6 serves as a tonic suppressor of NAD(P)H oxidase expression and activation, as inhibition of NAD(P)H oxidase improved endothelial function in SIRT6 haploinsufficient mice. Collectively, SIRT6 activation and/or histone acetyltransferase inhibition may be useful therapeutic approaches to reduce endothelial dysfunction and combat age-associated cardiovascular disease.

Anoxia Rapidly Induces Changes in Expression of a Large and Diverse Set of Genes in Endothelial Cells

“…In addition to this mechanism, in human mesenchymal cells, SIRT6 can prevent oxidative stress by transactivating NRF2-regulated antioxidant genes, including heme oxygenase 1 [ 85 ]. Finally, the increased levels of NADPH observed in SIRT6-overexpressing cells is in line with a recent report demonstrating that SIRT6 inhibits NADPH oxidase expression and activity in endothelial cells [ 86 ].…”

Mammalian Sirtuins and Their Relevance in Vascular Calcification

“…A new study showed SIRT6 could act on and deacetylate caveolin-1 in ECs, which activated autophagic degradation of caveolin-1 and inhibited high glucose stimulated LDL transport, which further inhibited the formation of atherosclerosis in diabetes ( Zhao et al, 2022 ). Greiten et al also confirmed that SIRT6 can prevent oxidative stress, endothelial dysfunction, and vascular dysfunction ( Greiten et al, 2021 ).…”

Effects of Hydroxytyrosol in Endothelial Functioning: A Comprehensive Review

“…Hydroxytyrosol acetate exerts an anti-inflammatory effect via the SIRT6-mediated PKM2 signaling pathway and inhibits TNF activity by TNF receptor superfamily member 1A (TNFRSF1A) signaling pathway [ 104 ]. Activation of SIRT6 improved endothelial function in haplo-insufficient mice by inhibiting NAD(P)H oxidase, which is responsible for oxidative stress [ 126 ]. Hydroxytyrosol also countered systemic inflammation in mice by inhibiting the expression of inflammatory markers, cyclooxygenase-2 (COX2), IL-1b, IL-6, and TNF-α via mediating the SIRT6/PKM2 signaling pathway [ 85 ].…”