Endothelium-specific SIRT1 overexpression inhibits hyperglycemia-induced upregulation of vascular cell senescence

Abstract

The rapidly increasing prevalence of diabetes mellitus worldwide is one of the most serious and challenging health problems in the 21st century. Mammalian sirtuin 1 (SIRT1) has been shown to decrease high-glucose-induced endothelial cell senescence in vitro and prevent hyperglycemia-induced vascular dysfunction. However, a role for SIRT1 in prevention of hyperglycemia-induced vascular cell senescence in vivo remains unclear. We used endothelium-specific SIRT1 transgenic (SIRT1-Tg) mice and wild-type (WT) mice to construct a 40-week streptozotocin (STZ)-induced diabetic mouse model. In this mode, 42.9% of wild-type (WT) mice and 38.5% of SIRT1-Tg mice were successfully established as diabetic. Forty weeks of hyperglycemia induced significant vascular cell senescence in aortas of mice, as indicated by upregulation of expression of senescence-associated markers including p53, p21 and plasminogen activator inhibitor-1 (PAI-1). However, SIRT1-Tg diabetic mice displayed dramatically decreased expression of p53, p21 and PAI-1 compared with diabetic WT mice. Moreover, manganese superoxide dismutase expression (MnSOD) was significantly downregulated in the aortas of diabetic WT mice, but was preserved in diabetic SIRT1-Tg mice. Furthermore, expression of the oxidative stress adaptor p66Shc was significantly decreased in aortas of SIRT1-Tg diabetic mice compared with WT diabetic mice. Overall, these findings suggest that SIRT1-mediated inhibition of hyperglycemia-induced vascular cell senescence is mediated at least partly through the reduction of oxidative stress. SIRT1, hyperglycemia, vascular cell senescence Citation:Chen H Z, Wan Y Z, Zhou S, et al. Endothelium-specific SIRT1 overexpression inhibits hyperglycemia-induced upregulation of vascular cell senescence.

Sirt1, a Negative Regulator of Matrix Metalloproteinase-9 in Diabetic Retinopathy

“…50 Overexpression of Sirt1 is shown to prevent increase in oxidative stress markers. 51 Here, we show that regulation of Sirt1 by resveratrol inhibits glucose-induced increase in ROS and also prevents mitochondria damage, as evidenced by significantly higher expression of mtDNA-encoded Cytb in glucose-treated cells incubated with resveratrol compared with the cells without resveratrol. Consistent with our results, Sirt1 has been shown to regulate mitochondria homeostasis.…”

Enhanced Viral Replication by Cellular Replicative Senescence

“…SIRT1 has a broad range of physiological and biological functions, which play an important role in controlling gene expression, metabolism and aging (14). At cellular level, overexpression of SIRT1 was shown to prevent replicative senescence (15). Recent studies by Koyuncu et al identified SIRT1 as an ancient antiviral defense factor (16).…”

SIRT 1‐mediated epigenetic downregulation of plasminogen activator inhibitor‐1 prevents vascular endothelial replicative senescence

“…Previous studies have shown that SIRT1 plays a critical role in the endothelial-dependent control of the vascular tone (Mattagajasingh et al ., 2007; Zhang et al ., 2008; Zhou et al ., 2011) and a protective role in atherosclerotic vascular diseases (Zhang et al ., 2008; Stein et al ., 2010; Gorenne et al ., 2013). Moreover, SIRT1 overexpression or activation in endothelial cells displays protective effects on oxidative stress-induced premature senescence (Ota et al ., 2007, 2008; Kao et al ., 2010; Zu et al ., 2010; Chen et al ., 2012). However, it remains unclear whether SIRT1 prevents replicative vascular senescence and by which SIRT1 facilitates the effects of antireplicative senescence.…”