Abstract 10751: NADPH Oxidase - a Therapeutic Target to Restore Endothelial Function in Insulin Resistance
Insulin resistance (IR) plays pivotal role in the development and progression of a number disorders of human health including type 2 diabetes. A hallmark of IR is reduced bioavailability of the antiatherosclerotic signalling radical nitric oxide (NO). A common mechanism of reduced NO is enhanced degradation by reactive oxygen species (ROS) which are increased in IR humans and preclinical models of IR. In IR, superoxide anions, one of the major ROS is generated at levels exceeding their homeostatic threshold principally by NADPH oxidases. We aimed to examine the therapeutic potential of reducing NADPH oxidase derived superoxide anions in IR. Two IR murine models models, 1. Endothelial Specific Mutated Insulin Receptor Over-expression (ESMIRO), a model of endothelium specific IR. 2. heterozygous Insulin Receptor KnockOut (IRKO) a model of whole body IR were used to examine the effect of pharmacological inhibition of NADPH oxidase on endothelial function and ROS production. Basal superoxide anion levels in isolated pulmonary endothelial cells (PEC), measured by lucigenin enhanced chemiluminescence, were increased in both models (130% increase for ESMIRO and 220% increase for IRKO compared to wild type, both p<0.01). Pre-treatment of PEC with gp91ds-tat, a cell permeable peptide, which specifically blocks NADPH oxidase subunit assembly and thus its function, restored superoxide anion levels to that of wild type. (Scrambled peptide did not have any effect). Endothelial NO mediated vasorelaxation in the aortae of both ESMIRO and IRKO, were impaired (101±11% relaxation with 1000 nM acetylcholine in wild type Vs 61±3% in ESMIRO (n=5,p<0.01); 91±3% relaxation in wild type Vs 75±6% in IRKO. (n=4, p=0.03)). This effect was reversed upon incubating aortic rings in gp91-ds tat peptide for 30 minutes. These data demonstrate that in 2 different but complementary models of IR, there is enhanced superoxide anion production, leading to reduced bioavailability of NO. Inhibiting NADPH oxidase reduces superoxide anions to wild type levels and restores aortic vasorelaxation responses. This study supports NADPH oxidase as a target to increase NO bioavailability in IR.
- © 2011 by American Heart Association, Inc.