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(Circulation. 2003;107:3073.)
© 2003 American Heart Association, Inc.

Basic Science Reports

Lack of Insulin Receptor Substrate-2 Causes Progressive Neointima Formation in Response to Vessel Injury

Tetsuya Kubota, MD; Naoto Kubota, MD, PhD; Masao Moroi, MD, PhD; Yasuo Terauchi, MD, PhD; Tsuneo Kobayashi, PhD; Katsuo Kamata, PhD; Ryo Suzuki, MD, PhD; Kazuyuki Tobe, MD, PhD; Atsushi Namiki, MD, PhD; Shinichi Aizawa, PhD; Ryozo Nagai, MD, PhD; Takashi Kadowaki, MD, PhD; Tetsu Yamaguchi, MD, PhD

From the Third Department of Internal Medicine, Toho University School of Medicine, Ohashi Hospital, Tokyo, Japan (T.K., M.M., A.N., T.Y.); the Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan (N.K., Y.T., R.S., K.T., T.K.); the Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Tokyo, Japan (T.K., K.K.); the Laboratory for Animal Resources and Genetic Engineering Center for Developmental Biology, RIKEN Kobe, Hyogo, Japan (S.A.); and the Department of Cardiovascular Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan (R.N.).

Correspondence to Dr Masao Moroi, Third Department of Internal Medicine, Toho University School of Medicine, Ohashi Hospital 2-17-6 Ohashi, Meguro-ku, Tokyo 153-8515, Japan. E-mail moroi{at}med.toho-u.ac.jp

Background— Insulin resistance is associated with atherosclerosis, but its mechanism is unknown. It has been reported that insulin receptor substrate (IRS)-1 deficient (IRS-1^-/-) mice showed insulin resistance without type 2 diabetes, whereas the IRS-2 deficient (IRS-2^-/-) mice showed insulin resistance with type 2 diabetes.

Methods and Results— We investigated neointima formation in the IRS-1^-/- and IRS-2^-/- mice at 8 and 20 weeks. The IRS-2^-/- mice showed much greater neointima formation than the IRS-1^-/- and wild-type mice at 8 weeks. At 20 weeks, the IRS-2^-/- mice had greater neointima formation than the IRS-1^-/- mice, which showed more enhanced neointima formation than the wild-type mice. The IRS-1^-/- and IRS-2^-/- mice had dyslipidemia, hypertension, and insulin resistance. The IRS-2^-/- mice had more metabolic abnormalities than the IRS-1^-/- mice at 8 and 20 weeks. IRS-2 expression was detected, but IRS-1 expression was not detected in the vessels.

Conclusions— The neointima formation in the IRS-1^-/- and IRS-2^-/- mice appears to be related to abnormalities induced by the altered metabolic milieu in insulin-resistant states. Moreover, because neointima formation was much greater in the IRS-2^-/- mice than in the IRS-1^-/- mice at 8 and 20 weeks, it is suggested that a lack of IRS-2 renders the vasculature more susceptible to injury in the abnormal metabolic milieu, and IRS-2 may have a protective effect on neointima formation. We conclude that IRS-2 is protective and retards the development of neointima formation in insulin-resistant states.

Key Words: atherosclerosis • insulin • vessels • risk factors

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