Abstract 17106: Nox2-derived Reactive Oxygen Species Impede Vascular Repair in the Context of Endothelium-specific Insulin Resistance

Introduction: Insulin resistance is independently linked to cardiovascular disease, and oxidative stress is recognised as a potential contributor to this relationship. We have previously shown that endothelium-specific insulin resistance promotes endothelial dysfunction, atherosclerosis, and increased vascular NADPH oxidase 2 (NOX2) derived reactive oxygen species (ROS). Oxidative stress may promote vascular disease by impairing endogenous vascular repair. Hypothesis: We hypothesise that deletion of NOX2 in mice with endothelial specific insulin resistance can improve vascular repair. Methods: Mice with endothelial specific insulin resistance (ESMIRO) were bred with mice deficient in NOX2, in order to produce double-cross ESMIRO x NOX2y/- (ExN) offspring. Phenotypic assessment comprised glucose and insulin tolerance tests and ELISA for plasma insulin concentration. In vivo assessment of vascular repair and angiogenesis were undertaken using femoral artery wire injury and hindlimb ischaemia techniques, respectively, whilst flow cytometry was used to quantify circulating progenitor cells (CPCs). Data are expressed as mean [standard error] and compared using unpaired t-tests; *=p Results: No significant differences were seen between ExN and ESMIRO in glucose tolerance, insulin sensitivity, or basal insulin level (0.8[0.1]ng/ml vs. 0.8[0.1];p=0.8). ExN mice demonstrated significantly improved vascular regeneration following injury compared to ESMIRO (62%[4%] vs. 46%[3%]*), coupled with a significantly higher number of CPCs (202.6[20.3] per 100000 lymphocytes vs. 134.3[10.6]*). This improvement was not mirrored in ischaemic limb perfusion recovery (Perfusion relative to non-ischaemic limb at 28 days 54%[8%] vs. 53%[4%]). Conclusions: Our data demonstrate that targeting NOX2 can augment vascular repair in the setting of endothelial specific insulin resistance, whilst having no detrimental impact on the response to limb ischaemia, and is associated with an increased abundance of CPCs. These findings support a possible role for NOX2 inhibitors to promote recovery from vascular injury in the setting of insulin resistance.