Abstract 15394: Insulin Induced Uncoupling of Nitric Oxide Synthase and Generation of Reactive Oxygen Species Underlie Cerebrovascular Insulin Resistance
Objective. Insulin resistance (IR) accompanied by hyperinsulinemia is an independent risk factor for stroke. However, the cerebrovascular actions of insulin in IR or diabetes have never been examined. We hypothesized that insulin would elicit adverse cerebrovascular responses in Zucker obese rats (ZO) with IR compared to Zucker lean control rats (ZL).
Research Design And Methods. Diameter measurements, fluorescence microscopy and immunoblot studies were performed in the isolated cerebral arteries.
Results. Insulin induced dose-dependent cerebrovascular vasodilation that was diminished in ZO compared to ZL. Denudation of endothelium revealed vasoconstriction to insulin that was greater in ZO compared to ZL. Inhibition of nitric oxide synthase (NOS) diminished vasodilation to insulin in ZL but paradoxically improved vasodilation in ZO. Inhibition of neuronal NOS, scavenging of reactive oxygen species (ROS) of mitochondrial and cytosolic origin, tetrahydrofolate (BH4) precursor supplementation, and inhibition of NADPH oxidase or COX, all improved cerebral vasodilation in response to insulin in ZO. Insulin-induced phosphorylation of Akt and endothelial NOS were diminished, but phosphorylation of PKC and ERK were enhanced in ZO arteries. Enhanced GTP cyclohydrolase-I (GTP-CH) expression at baseline and in response to insulin was reduced in ZO arteries. Fluorescence studies confirmed increased ROS in ZO arteries at baseline and in response to insulin that was sensitive to NOS inhibition and BH4 supplementation.
Conclusions. Cerebrovascular IR in ZO rats results from a vicious cycle involving decreased NO bioavailability and increased ROS, perpetuated by insulin-induced activation of NADPH oxidase, COX and mitochondrial ROS generation leading to NOS uncoupling. Insulin-instigated oxidative degradation of BH4 and impaired insulin-induced regeneration of BH4 by GTP-CH independently promoted NOS uncoupling
- © 2011 by American Heart Association, Inc.