Induction of Endothelial Nitric Oxide Synthase, SIRT1, and Catalase by Statins Inhibits Endothelial Senescence Through the Akt Pathway

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 30; no. 11; pp. 2205 - 2211
• Main Authors: Ota, Hidetaka, Eto, Masato, Kano, Mitsunobu R, Kahyo, Tomoaki, Setou, Mitsutoshi, Ogawa, Sumito, Iijima, Katsuya, Akishita, Masahiro, Ouchi, Yasuyoshi
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.11.2010; Lippincott Williams & Wilkins
• Subjects: Animals; Atherosclerosis (general aspects, experimental research); Atorvastatin Calcium; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Catalase - biosynthesis; Cellular Senescence - drug effects; Coronary heart disease; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endothelial Cells - drug effects; Heart; Heptanoic Acids - pharmacology; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Male; Medical sciences; Mice; Nitric Oxide Synthase Type III - biosynthesis; Nitric Oxide Synthase Type III - physiology; Oxidative Stress - drug effects; Pravastatin - pharmacology; Proto-Oncogene Proteins c-akt - physiology; Pyrroles - pharmacology; Quinolines - pharmacology; Sirtuin 1 - biosynthesis; Sirtuin 1 - physiology; Umbilical Veins; Senescence; Enzyme; Cardiovascular disease; Statin derivative; SIRT1; Nitric-oxide synthase; Endothelium; Vascular disease; Peroxidases; Catalase; statin; Atherosclerosis; Oxidoreductases; nitric oxide synthase; Antilipemic agent
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/ATVBAHA.110.210500

OBJECTIVE—Statins (3-hydroxy-3-methylglutaryl–coenzyme A reductase inhibitors) have pleiotropic vascular protective effects besides cholesterol lowering. Recently, experimental and clinical studies have indicated that senescence of endothelial cells is involved in endothelial dysfunction and atherogenesis. Therefore, the present study was performed to determine whether statins would reduce endothelial senescence and to clarify the molecular mechanisms underlying the antisenescent property of statins. METHODS AND RESULTS—Senescent human umbilical vein endothelial cells were induced by hydrogen peroxide (H2O2), as judged by senescence-associated β-galactosidase assay and cell morphological appearance. Atorvastatin, pravastatin, and pitavastatin inhibited the oxidative stress induced-endothelial senescence. These statins phosphorylated Akt at Ser473 and subsequently led to increased expression of endothelial nitric oxide synthase (eNOS), SIRT1, and catalase. Treatment with LY294002 or Akt short interfering RNA decreased the eNOS activation, SIRT1 expression, and antisenescent property of atorvastatin. Moreover, in streptozotocin-diabetic mice, administration of pitavastatin increased eNOS, SIRT1, and catalase expression and decreased endothelial senescence, but levels remained unaltered in Sirt1 knockout mice. CONCLUSION—Our results indicate that treatment with statins inhibits endothelial senescence and that enhancement of SIRT1 plays a critical role in prevention of endothelial senescence through the Akt pathway, a direct target of statins.