Obesity induced Endothelial Dysfunction and Vascular Oxidative Stress: Contributions of Xanthine Oxidase.

NICHOLAS K.H. KHOO, GABOR CSANYI, GUSTAVO R. BONACCI, BRUCE A. FREEMAN, AND ERIC E. KELLEY

Orlando, FL

Congreso; SFRBM's 17th Annual Meeting; 2010

Society for Free Radical Biology & Medicine

Obesity-induced abnormal cytokine production and activation of inflammatory signaling pathways is seminal to the pathogenesis of insulin resistance (IR), type 2 diabetes (T2D) and related cardiovascular complications. Underscoring the progression of these deleterious effects of obesity is increased levels of reactive oxygen species (ROS). For example, ROS-driven endothelial dysfunction is significantly enhanced by the hypoxic and hyperglycemic environments in vessels of diabetic patients. One proposed source of these ROS is xanthine oxidase (XO), with elevated XO activity reported in plasma both clinically and in animal models of T2D. However, neither the species/quantity of XO-derived ROS nor their contribution to T2D-mediated vascular pathology has been defined. We report increased XO activity in plasma, aorta, heart, liver, fat, muscle and kidney from mice on a high-fat diet (HFD) compared to mice on normal chow (NC). Treatment with the potent XO-specific inhibitor, Uloric (Ki = 0.12 nM vs. 6.0 μM for allopurinol) abrogated HFD-mediated increases in XO activity. Both, EPR spin trapping and immunospin trapping demonstrated Uloric-inhibitable enhancement of vascular ROS formation in HFD mice. The functional assessment of mouse aortic rings revealed HFD impaired vasorelaxation (>55%) in response to acetylcholine (Ach). Treatment of HFD mice with Uloric completely restored response to Ach compared to NC mice whereas allopurinol provided only 40% restoration. Furthermore, studies under conditions more reflective of the vasculature (aeration with 15% vs. 95% O2) revealed no alteration in vessel response upon exposure to SOD. This suggests a role for H2O2, the major (~80%) product of XO/O2 reaction at this O2 tension. Into, these data demonstrate a critical role for XO-derived ROS in T2D-induced vascular pathology and suggest novel XO-specific inhibition to be an effective treatment strategy.