Insulin-Induced Generation of Reactive Oxygen Species and Uncoupling of Nitric Oxide Synthase Underlie the Cerebrovascular Insulin Resistance in Obese Rats
Open Access
- 11 January 2012
- journal article
- Published by SAGE Publications in Journal of Cerebral Blood Flow & Metabolism
- Vol. 32 (5), 792-804
- https://doi.org/10.1038/jcbfm.2011.181
Abstract
Hyperinsulinemia accompanying insulin resistance (IR) is an independent risk factor for stroke. The objective is to examine the cerebrovascular actions of insulin in Zucker obese (ZO) rats with IR and Zucker lean (ZL) control rats. Diameter measurements of cerebral arteries showed diminished insulin-induced vasodilation in ZO compared with ZL. Endothelial denudation revealed vasoconstriction to insulin that was greater in ZO compared with ZL. Nonspecific inhibition of nitric oxide synthase (NOS) paradoxically improved vasodilation in ZO. Scavenging of reactive oxygen species (ROS), supplementation of tetrahydrobiopterin (BH4) precursor, and inhibition of neuronal NOS or NADPH oxidase or cyclooxygenase (COX) improved insulin-induced vasodilation in ZO. Immunoblot experiments revealed that insulin-induced phosphorylation of Akt, endothelial NOS, and expression of GTP cyclohydrolase-I (GTP-CH) were diminished, but phosphorylation of PKC and ERK was enhanced in ZO arteries. Fluorescence studies showed increased ROS in ZO arteries in response to insulin that was sensitive to NOS inhibition and BH4 supplementation. Thus, a vicious cycle of abnormal insulin-induced ROS generation instigating NOS uncoupling leading to further ROS production underlies the cerebrovascular IR in ZO rats. In addition, decreased bioavailability and impaired synthesis of BH4 by GTP-CH induced by insulin promoted NOS uncoupling.Keywords
This publication has 38 references indexed in Scilit:
- IMPACT OF OBESITY AND INSULIN RESISTANCE ON VASOMOTOR TONE: NITRIC OXIDE AND BEYONDClinical and Experimental Pharmacology and Physiology, 2006
- Rosuvastatin improves cerebrovascular function in Zucker obese rats by inhibiting NAD(P)H oxidase-dependent superoxide productionAmerican Journal of Physiology-Heart and Circulatory Physiology, 2006
- Impaired endothelin-induced vasoconstriction in coronary arteries of Zucker obese rats is associated with uncoupling of [Ca2+]isignalingAmerican Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2006
- Type 2 Diabetic Mice Have Increased Arteriolar Tone and Blood PressureArteriosclerosis, Thrombosis, and Vascular Biology, 2005
- Impaired insulin-induced vasodilation in small coronary arteries of Zucker obese rats is mediated by reactive oxygen speciesAmerican Journal of Physiology-Heart and Circulatory Physiology, 2005
- Oxidant stress and constrictor reactivity impair cerebral artery dilation in obese Zucker ratsAmerican Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2005
- Sepiapterin Decreases Vasorelaxation in Nitric Oxide Synthase Inhibition–Induced HypertensionJournal of Cardiovascular Pharmacology, 2004
- Insulin resistance and classic risk factors in type 2 diabetic patients with different subtypes of ischemic stroke.Diabetes Care, 1999
- Modulation of vasoconstriction by insulin.1998
- Evaluation of the relative contribution of nitric oxide and peroxynitrite to the suppression of mitochondrial respiration in immunostimulated macrophages using a manganese mesoporphyrin superoxide dismutase mimetic and peroxynitrite scavengerFEBS Letters, 1996