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(Circulation. 2005;111:1398-1406.)
© 2005 American Heart Association, Inc.

Molecular Cardiology

Blockade of Endogenous Cytokines Mitigates Neointimal Formation in Obese Zucker Rats

Ryo Takeda, MD; Etsu Suzuki, MD; Hiroshi Satonaka, MD; Shigeyoshi Oba, MD; Hiroaki Nishimatsu, MD; Masao Omata, MD; Toshiro Fujita, MD; Ryozo Nagai, MD; Yasunobu Hirata, MD

From the Departments of Internal Medicine (R.T., E.S., H.S., S.O., M.O., T.F., R.N., Y.H.) and Urology (H.N.), Faculty of Medicine, University of Tokyo, Tokyo, Japan.

Correspondence to Etsu Suzuki, MD, Division of Nephrology and Endocrinology No. 202, Department of Internal Medicine, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail suzuki-2im{at}h.u-tokyo.ac.jp

Received June 14, 2004; revision received November 6, 2004; accepted November 17, 2004.

Background— It is well known that diabetes mellitus is a major risk factor for vascular diseases such as atherosclerosis and restenosis after angioplasty. It has become clear that advanced glycation end products (AGE) and their receptor (RAGE) are implicated in vascular diseases, especially in diabetes mellitus. Nevertheless, the mechanisms by which diabetes mellitus is often associated with vascular diseases remain unclear.

Methods and Results— To study the role of endogenous cytokines such as tumor necrosis factor- (TNF-) and interleukin-6 in the development of vascular diseases and in the expression of RAGE, we used semapimod, a pharmacological inhibitor of cytokine production, and examined its effect on neointimal formation in the femoral artery of obese Zucker (OZ) rats. We also used an adenovirus construct expressing a dominant negative mutant of the receptor for TNF- (AdTNFRC) to block the action of endogenous TNF-. Semapimod significantly suppressed neointimal formation and RAGE expression in OZ rats compared with untreated OZ rats. This inhibitory effect of semapimod on neointimal formation was overcome by infection of an adenovirus expressing RAGE into the femoral artery of OZ rats. Furthermore, AdTNFRC infection significantly suppressed neointimal formation and RAGE expression in the femoral artery of OZ rats.

Conclusions— These results suggest that endogenous cytokines, especially TNF-, were implicated in neointimal formation in OZ rats and that RAGE was a mediator of the effect of these cytokines on neointimal formation.

Key Words: diabetes mellitus • angioplasty • gene therapy

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