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

Abstract

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. (Hypertension. 2007;50:384-391.)

Continuous Activation of Renin-Angiotensin System Impairs Cognitive Function in Renin/Angiotensinogen Transgenic Mice

“…Yamamoto et al 35 reported previously that reactive oxygen species produced by Ang II-activated NADPH oxidase increased cerebral neuronal apoptosis and inflammation in stroke-prone spontaneously hypertensive rats. Moreover, Wei et al 27 reported that NADPH oxidase contributed to vascular inflammation, endothelial dysfunction, and remodeling in transgenic (mRen2)27 rats, which exhibit elevated tissue Ang II, similar to our experimental model, hRN/hANG-Tg mice. It has been recognized that oxidative stress is implicated in age-related cognitive impairment.…”

“…Ang II induces cerebrovascular remodeling, promotes vascular inflammation and oxidative stress, and thereby impairs the regulation of CBF. 26,27 Previous studies showed that endothelial function in cerebral vessels was impaired in a genetic model of Ang II-dependent hypertension. 13,28 It is known that CBF decreases with aging.…”

Identification of Bona Fide Alternative Renin Transcripts Expressed Along Cortical Tubules and Potential Roles in Promoting Insulin Resistance In Vivo Without Significant Plasma Renin Activity Elevation

“…In earlier days, it was demonstrated that enhanced kinetics of the reaction between mouse renin and rat angiotensinogen are one of pathophysiological mechanism for this model. 39,40 Recently, this animal model was reported to have various pathophysiological features such as insulin resistance, [41][42][43] left ventricular dysfunction, 44,45 nonalcoholic fatty liver disease-like significant hepatic steatosis with increased hepatic reactive oxygen species, lipid peroxidation, steatohepatitis, and fibrosis 46 as a result of tissue RAS overactivation. We generated transgenic ARen2 overexpression mice with a C57BL/6J background, which endogenously have only the Ren1C renin gene.…”

Atorvastatin Prevents Angiotensin II–Induced Vascular Remodeling and Oxidative Stress

“…[5][6][7] In fact, ROS have been shown to play a critical role in hypertrophy, fibrosis, and remodeling in the heart and vasculature. 6,8,9 Statins are inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A reductase, a ubiquitous enzyme critical for the biosynthesis of cholesterol. Several clinical trials have demonstrated that statins exert beneficial effects in patients at high cardiovascular risk.…”