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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:889.)
© 2009 American Heart Association, Inc.

Cell Biology/Signaling

Protective Role of SIRT1 in Diabetic Vascular Dysfunction

Masayuki Orimo; Tohru Minamino; Hideyuki Miyauchi; Kaoru Tateno; Sho Okada; Junji Moriya; Issei Komuro

From the Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Japan.

Correspondence to Issei Komuro, MD, PhD, Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. E-mail komuro-tky{at}umin.ac.jp

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⁺-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.

Conclusions— These findings represent a novel mechanism of vascular cell senescence induced by hyperglycemia and suggest a protective role of SIRT1 in the pathogenesis of diabetic vasculopathy.

The pathological role of SIRT1 is not yet fully understood. Hyperglycemia decreases SIRT1 expression and thus accelerates endothelial senescence. Activation of SIRT1 prevents the hyperglycemia-induced endothelial senescence and thereby protects against vascular dysfunction in mice with diabetes. These results suggest a protective role of SIRT1 in the pathogenesis of diabetic vasculopathy.

Key Words: cellular senescence • p53 • diabetes