Opportunity “Nox”: A Novel Approach to Preventing Endothelial Dysfunction in the Context of Insulin Resistance

Cardiovascular complications are more prevalent in individuals with conditions associated with insulin resistance. Knowledge is evolving concerning the mechanistic link between insulin resistance and vascular disease, but complete clarity does not exist. This is a high-priority area of investigation because individual and societal costs associated with diabetic vascular complications are increasing, and the need to elucidate effective therapeutic targets and intervention strategies with minimal off-target side effects is urgent. Insulin-resistant conditions such as type 2 diabetes and diet-induced obesity are associated with an altered endothelial cell phenotype, i.e., endothelial dysfunction. A crucial component of endothelial cell dysfunction is reduced nitric oxide (NO) bioavailability. Reduced NO bioavailability contributes importantly to pathologies specific to large (atherosclerosis, cardiomyopathy) and small (retinopathy, nephropathy, neuropathy) blood vessels (1). Oxidative stress, hyperglycemia, lipotoxicity, activation of the renin-angiotensin system, and increased proinflammatory cytokines are systemic disturbances in patients with conditions associated with insulin resistance. Each of these factors contributes independently and synergistically to decreasing NO bioavailability by impairing its synthesis and/or by enhancing its degradation (2). In this issue of Diabetes , Sukumar et al. (3) demonstrate that endothelial cell–specific insulin resistance increases NADPH oxidase (Nox) isoform 2 (Nox2) expression to an extent that elevates superoxide anion (O2·−) production and precipitates endothelial dysfunction. Reactive oxygen species (ROS) are highly reactive metabolites of oxygen that participate in oxidation-reduction reactions (4). A traditional definition of oxidative stress is when ROS accumulation overwhelms the cellular antioxidant defense mechanisms and the redox state of the biological compartment is shifted toward one that is more oxidizing (5,6). Cellular sources of ROS include NADPH-dependent oxidases, xanthine oxidase, lipoxygenases, mitochondrial oxidases, and NO synthases (7). Nox is a major source of O2·− in insulin-resistant humans (8,9) and …