on June 16, 2003
Published online before print June 16, 2003, doi: 10.1161/01.CIR.0000070937.52035.25
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Submitted on December 14, 2002
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.). * To whom correspondence should be addressed. 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.
Revised on March 14, 2003
Accepted on March 17, 2003
Lack of Insulin Receptor Substrate-2 Causes Progressive Neointima Formation in Response to Vessel Injury
Tetsuya Kubota MD,
Key words: atherosclerosis • insulin • vessels • risk factors
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