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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:760.)
© 2005 American Heart Association, Inc.

Vascular Biology

Insulin Signaling in Arteries Prevents Smooth Muscle Apoptosis

T. Nakazawa; T. Chiba; E. Kaneko; K. Yui; M. Yoshida; K. Shimokado

From the National Cardiovascular Center Research Institute (T.N., T.C., K.S.), Osaka; First Institute of New Drug Discovery, Otsuka Pharmaceutical Co., Ltd. (T.N.), Tokushima; and Tokyo Medical and Dental University Graduate School (T.N., T.C., E.K., K.Y., M.Y., K.S.), Tokyo, Japan.

Correspondence to Kentaro Shimokado, MD, Geriatrics and Vascular Medicine, Tokyo Medical and Dental University Graduate School, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519 Japan. E-mail k.shimoka.vasc{at}tmd.ac.jp

Objective— Insulin is an antiapoptotic factor of cultured vascular cells, but it is not clear whether it also exerts antiapoptotic effects on vascular cells in vivo. We studied insulin receptor signaling in the arteries of normal and diabetic rats to establish whether insulin exhibits antiapoptotic activity toward vascular smooth muscle cells in vivo as well as in vitro.

Methods and Results— Western blot analysis and real-time polymerase chain reaction revealed - and ß-subunits of the insulin receptor in association with insulin receptor substrate-1 and phosphatidylinositol 3-kinase in the media of the aorta and carotid artery. The insulin receptor signaling pathway was partially activated under physiological conditions, further activated by intravenous insulin injection, and was attenuated in streptozotocin-induced diabetic rats. Lipopolysaccharide injection induced more apoptosis of vascular smooth muscle cells in diabetic rats than in control rats, whereas insulin prevented apoptosis in the aortic wall. An in vitro study suggested that the antiapoptotic effect of insulin was mediated by phosphatidylinositol 3-kinase.

Conclusions— Insulin is an antiapoptotic factor of vascular smooth muscle cells in vitro and in vivo. Decreased insulin activity on the artery may increase smooth muscle cell death and cause unstable plaque formation associated with diabetes.

Insulin is antiapoptotic for cultured vascular smooth muscle, but it is not clear whether insulin is antiapoptotic in vivo. We report here that insulin is antiapoptotic in vitro and in vivo. Decreased insulin action on the artery may cause unstable plaque formation in diabetes by increasing smooth muscle apoptosis.

Key Words: diabetic macroangiopathy • antiapoptotic effect of insulin • vascular smooth muscle cells • Akt/protein kinase B • phosphatidylinositol 3-kinase

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