Oxidative Stress Induces Endothelial Cell Senescence via Downregulation of Sirt6

Abstract

Accumulating evidence has shown that diabetes accelerates aging and endothelial cell senescence is involved in the pathogenesis of diabetic vascular complications, including diabetic retinopathy. Oxidative stress is recognized as a key factor in the induction of endothelial senescence and diabetic retinopathy. However, specific mechanisms involved in oxidative stress-induced endothelial senescence have not been elucidated. We hypothesized that Sirt6, which is a nuclear, chromatin-bound protein critically involved in many pathophysiologic processes such as aging and inflammation, may have a role in oxidative stress-induced vascular cell senescence. Measurement of Sirt6 expression in human endothelial cells revealed that H2O2 treatment significantly reduced Sirt6 protein. The loss of Sirt6 was associated with an induction of a senescence phenotype in endothelial cells, including decreased cell growth, proliferation and angiogenic ability, and increased expression of senescence-associated β-galactosidase activity. Additionally, H2O2 treatment reduced eNOS expression, enhanced p21 expression, and dephosphorylated (activated) retinoblastoma (Rb) protein. All of these alternations were attenuated by overexpression of Sirt6, while partial knockdown of Sirt6 expression by siRNA mimicked the effect of H2O2. In conclusion, these results suggest that Sirt6 is a critical regulator of endothelial senescence and oxidative stress-induced downregulation of Sirt6 is likely involved in the pathogenesis of diabetic retinopathy.

Sirtuin-6 Preserves R-spondin-1 Expression and increases Resistance of intestinal Epithelium to injury in Mice

“…A previous study identified that H 2 O 2 treatment results in marked reduction of Sirt6 in endothelial cells (39). Consistent with these previous findings, our data indicate that mucosal Sirt6 protein expression is decreased in colitis.…”

SIRT1 and SIRT6 Signaling Pathways in Cardiovascular Disease Protection

“…2). Evidence of SIRT6 involvement in vascular protection comes from several studies showing that SIRT6 deficiency raises the expression of endothelial proinflammatory cytokines and increases NF-jB transcriptional activity (16,41,97,109). The protective effect of SIRT6 against premature endothelial senescence is exerted through a fine control of the expression of intercellular adhesion molecule-1 (ICAM-1), PAI-1, p21…”

“…In ECs, downregulation of SIRT6 occurs during hydrogen peroxide-induced cell senescence, whereas SIRT6 overexpression partially reverses this process (109). SIRT6 knockdown determines an accelerated cell senescence and overactive NF-jB signaling, thus disclosing the critical role of SIRT6 on aging and inflammation (211).…”

Nicotinamide Riboside Delivery Generates Nad+ Reserves to Protect Vascular Cells Against Oxidative Damage

“…Previous studies have reported SIRT1 implicated in age-associated senescent phenotype in vascular endothelial cells (141)(142)(143)(144). Similarly, SIRT6 deficiency has been linked to oxidative stressinduced senescence in endothelial cells (180). In Fig.…”

“…H 2 O 2 -induced oxidative stress has been reported to push endothelial cells towards a senescent phenotype through SIRT6 down-regulation (180). Further, a reported increased methylation state of sirt6 gene in humans with aging (age 20-79) suggests age-related repressed gene expression (181).…”