Rosuvastatin improves cerebrovascular function in Zucker obese rats by inhibiting NAD(P)H oxidase-dependent superoxide production

Abstract

Insulin-resistance induces cerebrovascular dysfunction and increases the risk for stroke. We investigated whether rosuvastatin (RSV), a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, can reverse reduced cerebrovascular responsiveness in insulin-resistant rats. Dilator responses of the basilar artery (BA) were examined after 1-day or 4-wk RSV (2 mg.kg(-1).day(-1)) treatment in anesthetized 12-wk-old insulin-resistant Zucker obese (ZO) and lean (ZL) rats by using a cranial window preparation. Vehicle-treated ZO rats had significantly higher fasting insulin, total cholesterol (TC), and triglyceride (TG) levels compared with ZL rats. In addition, in the ZO rats, dilator responses of the BA to acetylcholine, iloprost, cromakalim, and potassium chloride were significantly reduced when compared with ZL rats. One-day RSV treatment improved dilator responses of the ZO BAs without altering lipid levels. Four-week RSV treatment lowered both TC and TG by 30% and also improved dilator responses of the ZO BAs, although without additional effects compared with the 1-day RSV treatment. NAD(P)H oxidase-dependent superoxide production was significantly higher in the cerebral arteries of vehicle-treated ZO rats compared with ZL rats, but both 1-day and 4-wk RSV treatments normalized elevated superoxide levels in the ZO arteries. These findings demonstrate that RSV improves cerebrovascular function in insulin-resistance independently from its lipid-lowering effect by the inhibition of NAD(P)H oxidase.

Insulin-Induced Generation of Reactive Oxygen Species and Uncoupling of Nitric Oxide Synthase Underlie the Cerebrovascular Insulin Resistance in Obese Rats

“…Previous data from our laboratory (Erdos et al, 2004(Erdos et al, , 2006 and others (Oltman et al, 2006;Phillips et al, 2005;Stepp, 2006) have shown that ZO rats develop IR with a metabolic profile very similar to the human condition. As reported previously (Erdos et al, 2004(Erdos et al, , 2006, at 10 to 12 weeks of age, ZO rats had significantly greater body weight and exhibited features typical of metabolic syndrome including impaired glucose tolerance, hyperinsulinemia (widely used marker of IR), hypertriglyceridemia, and hypercholesterolemia. Importantly, young ZO rats used in the present study were insulin resistant but glucose levels and blood pressure were not elevated.…”

Effect of high-fat diet feeding on hypothalamic redox signaling and central blood pressure regulation

“…In addition, reports indicate that redox signaling mediates central AngII-induced cardiovascular responses. [6][7][8][9][10] As obesity is associated with systemic oxidative stress, 13,33 we hypothesized that HF diet-induced obesity could increase superoxide production and/or reduce antioxidant capacity in the brain resulting in elevated SNS activity and blood pressure. In this study, we found that NOX2, the main membrane-associated subunit of NADPH oxidase, and two regulatory subunits, p47 phox and p67 phox , are significantly upregulated in response to HF feeding in the hypothalamus resulting in increased NADPH oxidase activity.…”

Statins in Traumatic Brain Injury

“…10 In addition to reducing oxidative stress via downregulation of microglial activity, statins decreased the production of other harmful oxygen free radicals, such as superoxide, when baseline inflammation was present. 21 Various statins have been shown in large clinical trials to decrease systemic markers of inflammation, such as high sensitivity C-reactive protein. [22][23][24] However, clinical data in TBI remains preliminary.…”