Protective Role of SIRT1 in Diabetic Vascular Dysfunction

Abstract

Objective-Calorie restriction (CR) prolongs the lifespan of various species, ranging from yeasts to mice. In yeast, CR extends the lifespan by increasing the activity of silencing information regulator 2 (Sir2), an NAD ϩ -dependent deacetylase. SIRT1, a mammalian homolog of Sir2, has been reported to downregulate p53 activity and thereby prolong the lifespan of cells. Although recent evidence suggests a link between SIRT1 activity and metabolic homeostasis during CR, its pathological role in human disease is not yet fully understood. Methods and Results-Treatment of human endothelial cells with high glucose decreases SIRT1 expression and thus activates p53 by increasing its acetylation. This in turn accelerates endothelial senescence and induces functional abnormalities. Introduction of SIRT1 or disruption of p53 inhibits high glucose-induced endothelial senescence and dysfunction. Likewise, activation of Sirt1 prevents the hyperglycemia-induced vascular cell senescence and thereby protects against vascular dysfunction in mice with diabetes. Key Words: cellular senescence Ⅲ p53 Ⅲ diabetes T he NAD ϩ -dependent histone deacetylase Sir2 induces longevity in yeast in response to calorie restriction signals. 1 SIRT1, a mammalian homologue of Sir2 and a member of the Sir2 family called sirtuins, has been shown to target p53, 2-4 Ku70, 5 and the forkhead transcription factors 6 -8 for deacetylation, thereby regulating stress responses, apoptosis, and cellular senescence. Acetylation of p53 is known to be crucial for its stabilization and transcriptional activation. 9 Accumulating evidence suggests that SIRT1 also modulates the metabolism of glucose and fat by interacting with peroxisome proliferator-activated receptor (PPAR) ␥ through nuclear receptor corepressor to repress adipogenesis, 10 modifying PPAR ␥ coactivator-1␣ to regulate hepatic glucose homeostasis 11,12 and regulating insulin secretion levels as well as insulin sensitivity. [13][14][15] Treatment with the sirtuin activator resveratrol has been shown to improve diet-induced obesity and insulin resistance 16,17 and delay age-related deterioration including increased arterial stiffness. 18 Moreover, Sirt1 has been reported to control endothelial angiogenic functions during postnatal vascular growth. 19 However, it remains unclear whether SIRT1 is involved in the pathogenesis of diabetes and its complications including diabetic vasculopathy. Conclusions-TheseVascular cells have a finite lifespan when cultured and eventually undergo senescence. Many of the changes seen in senescent vascular cells are consistent with those that occur in age-related vascular diseases. 20,21 Moreover, senescent vascular cells have been detected in human atherosclerotic tissues and exhibit various functional abnormalities, 22 suggesting that senescence of vascular cells contributes to the pathophysiology of age-related vascular diseases. There is also in vivo evidence for the occurrence of vascular cell senescence in diabetic vasculopathy. 23 Given that CR augments SIRT1 activity...

Shear stress, SIRT1, and vascular homeostasis

“…Mattagajasingh et al (17) demonstrated that inhibition of SIRT1 in rat arteries attenuated endothelium-dependent vasodilation, which might be due to the enhanced acetylation of endothelial nitric oxide synthase (eNOS). In mice, RSV administration increased aortic eNOS activity (18). Furthermore, EC-specific overexpression of SIRT1 decreased atherosclerosis in ApoE-knockout mice (19).…”

Cardiovascular determinants of life span

“…resveratorl restores acetylated p53 and p21 in the aorta and thus improves endothelial dysfunction by down-regulating ICAM-1 expression and inhibiting leukocyte rolling [101], These data imply a protective role of SIRT1 in the pathogenesis of diabetic vascular dysfunction .…”

“…In Sirt1 knockout mice, insulin levels are reduced in both normoglycemic and glucose tolerance experiments. Consistently, in a type II diabetic mouse, genetic upregulation of SIRT1 [99,101] or treated with resveratorl [102], a small molecule activator of SIRT1, enhances insulin secretion and thus improves glucose tolerance.…”

“…Furthermore in the aorta of streptozotocin-induced diabetic mouse, the expression of SIRT1 protein is reduced accompanied by higher levels of acetylated p53 and p21 expression [101].…”

“…Resveratrol, one of the polyphenolic compounds in grapes and wine, is reported as a small molecule activator of SIRT1 [117,118]. Resveratrol increases insulin secretion in pancreatic β cell [102] and improves endothelial function in the aorta of diabetic mouse [101]. Besides, resveratrol reduces TNF-α-induced tissue factor expression through inactivating NF-κB mediate transcription [119] and thus prevents cells adhesiveness [120,121].…”