Evidence for a Causal Role of the Renin-Angiotensin System in Vascular Dysfunction Associated With Insulin Resistance

Abstract

Abstract-Excess production of superoxide anion in response to angiotensin II plays a central role in the transduction of signal molecules and the regulation of vascular tone. We examined the ability of insulin resistance to stimulate superoxide anion production and investigated the identity of the oxidases responsible for its production. Rats were fed diets containing 60% fructose (fructose-fed rats) or 60% starch (control rats) for 8 weeks. In aortic homogenates from fructose-fed rats, the superoxide anion generated in response to NAD(P)H was more than 2-fold higher than that of control rats. Pretreatment of the aorta from fructose-fed rats with inhibitors of NADPH oxidase significantly reduced superoxide anion production. In the isolated aorta, contraction induced by angiotensin II was more potent in fructose-fed rats compared with control rats. Losartan normalized blood pressure, NAD(P)H oxidase activity, endothelial function, and angiotensin II-induced vasoconstriction in fructose-fed rats. To elucidate the molecular mechanisms of the enhanced constrictor response to angiotensin II, expressions of angiotensin II receptor and subunits of NADPH oxidase were examined with the use of angiotensin II type 1a receptor knockout (AT1a KO) mice. Expression of AT1a receptor mRNA was enhanced in fructose-fed mice, whereas expression of either AT1b or AT2 was unaltered. In addition, protein expression of each subunit of NADPH oxidase was increased in fructose-fed mice, whereas the expression was significantly decreased in fructose-fed AT1a KO mice. The novel observation of insulin resistance-induced upregulation of AT1 receptor expression could explain the association of insulin resistance with endothelial dysfunction and hypertension. Key Words: insulin resistance Ⅲ angiotensin II Ⅲ angiotensin antagonist Ⅲ endothelium Ⅲ free radicals Ⅲ blood pressure T here is a growing body of evidence demonstrating the coexistence of hypertension in the insulin-resistant states, such as obesity and type 2 diabetes. 1-3 Impairment of vasomotor function in hypertension may be caused by an imbalance of vasodilating and vasoconstricting factors. 4 We have recently reported that insulin resistance may be a pathogenic factor for endothelial dysfunction through impaired endothelial NOS (eNOS) activity caused by the enhanced formation of superoxide anion (O 2 Ϫ ), which is caused by relative deficiency of tetrahydrobiopterin (BH 4 ) in vascular endothelial cells. 5 Although BH 4 supplementation results in the restoration of the endothelial function, BH 4 treatment did not normalize blood pressure and vascular oxidative stress in the insulin-resistant state. 6 These findings suggest that an additional element to regulate vascular tone is therefore likely to be present in the insulin-resistant state.Apart from the L-arginine-nitric oxide (NO) pathway, the vascular tone is regulated by a variety of autocrine and paracrine systems localized in the endothelium and smooth muscle cells. Blockade of the renin-angiotensin system with angiotensin-conv...

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