Published Online
on May 28, 2007

A more recent version of this article appeared on August 1, 2007

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Submitted on March 7, 2007
Revised on March 22, 2007

NADPH Oxidase Contributes to Vascular Inflammation, Insulin Resistance, and Remodeling in the Transgenic (mRen2) Rat

Yongzhong Wei; Adam T. Whaley-Connell; Kemin Chen; Javad Habibi; Grace M.-E. Uptergrove; Suzanne E. Clark; Craig S. Stump; Carlos M. Ferrario; and James R. Sowers^*

From the University of Missouri-Columbia (Y.W., A.T.W.-C., K.C., J.H., G.M.-E.U., S.E.C., J.R.S.), and the Harry S. Truman VA Medical Center (Y.W., A.T.W.-C., J.H., S.E.C., J.R.S.), Columbia, Mo; Tucson Arizona VA Medical Center (C.S.S.); and the Bowman Gray School of Medicine at Wake Forest University (C.M.F.), Winston-Salem, NC.

^* To whom correspondence should be addressed. E-mail: Sowersj{at}health.missouri.edu.

Abstract--Reduced insulin sensitivity is characteristic of various pathological conditions such as type 2 diabetes mellitus and hypertension. Angiotensin II, acting through its angiotensin type 1 receptor, inhibits the actions of insulin in the vasculature which may lead to deleterious effects such as vascular inflammation, remodeling, endothelial dysfunction, and insulin resistance. In contrast, insulin normally exerts vasodilatory, antiinflammatory, and prosurvival actions. To explore the impact of angiotensin II on insulin signaling, NADPH oxidase-derived reactive oxygen species formation, vascular inflammation, apoptosis, and remodeling, we used transgenic TG(mRen2)27 (Ren2) rats, which harbor the mouse renin transgene and exhibits elevated tissue angiotensin II levels. Compared with Sprague-Dawley controls, Ren2 aortas exhibited greater NADPH oxidase activity, reactive oxygen species levels, C-reactive protein, tumor necrosis factor- expression, apoptosis, and wall thickness, which were significantly attenuated by in vivo treatment with angiotensin type 1 receptor blockade (valsartan) or the superoxide dismutase/catalase mimetic (tempol). There was substantially diminished Akt and endothelial NO synthase activation in Ren2 aortas in response to in vivo insulin stimulation, and this was significantly improved by in vivo treatment with valsartan or tempol. In vivo treatment with valsartan, but not tempol, significantly reduced blood pressure in Ren2 rats. Further, there was reduced insulin induced Akt activation and increased tumor necrosis factor- levels in vascular smooth muscle cells from Ren2 and Sprague-Dawley rats treated with angiotensin II, abnormalities that were abrogated by angiotensin type 1 receptor blockade with valsartan or antioxidant N-acetylcysteine. Collectively, these data suggest that increased angiotensin type 1 receptor/NADPH oxidase activation/reactive oxygen species contribute to vascular insulin resistance, endothelial dysfunction, apoptosis, and inflammation.

Key words: Ren2 rat • NADPH oxidase • ROS • vascular inflammation • insulin resistance • apoptosis

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