Abstract 5523: Contribution of Ox-LDL Induced Arginase Activation to Vascular Dysfunction in Cigarette Smoke
Although Atherosclerotic Vascular Disease is a complex process resulting from numerous genetic and environmental factors, it is well recognized that oxidized low density lipoproteins (Ox-LDL) produces pro-atherogenic effects in endothelial cells by inducing the expression of adhesion molecules, apoptosis, superoxide anion formation, and impairing nitric oxide (NO) formation. Exposure to second hand smoke (SHS) further exacerbates this process by enhancing oxidation of LDL and increasing oxidant stress in the endothelium. Ox-LDL results in early endothelial arginase activation and later transcriptional upregulation with reciprocal decrease in NO and ED (endothelial dysfunction). We tested the hypothesis that ArgII and the lectin like OxLDL receptor (LOX) are critical in mediating the ED associated with SHS.
Methods/Results: Wild type (C57BL/6J, WT), LOX−/− and ArgII−/− male mice (3– 4 months old, n=6) were exposed to SHS (6 hrs/Day, 5 Days/Wk for 2 Wks; 2R4F reference cigarettes) obtaining WT-SHS, LOX−/−SHS and ArgII−/−SHS groups and C (control mice) were exposed to room air. Aorta from WT-SHS demonstrated a 2.5 fold induction of arginase activity vs C. Strikingly LOX−/− mice showed decreased SHS induced arginase activation. Vascular reactivity studies performed in organ chambers demonstrated that aortic rings isolated from WT-SHS exhibited markedly attenuated endothelium-dependent vasorelaxation as compared to WT C (78.80%±8 vs 46.58%±5). LOX−/−SHS (68.60%±3) showed less impairment in EF (endothelial function). EF was completely protected in ArgII−/−SHS vessels. ArgII−/−SHS vs WT C (67.48%±7 vs 78.80%±8). PWV (m/s), index of central aortic stiffness, measured by high frequency Doppler was significantly elevated in WT SHS vs C (4.13±0.11 vs 3.4±0.06). LOX−/−SHS (3.6±0.15) and ArgII−/−SHS (3.529±0.2131) demonstrated no significant increase in vascular stiffness.
Conclusion: The protection from injurious effects of smoking in LOX−/− and ArgII−/−mice demonstrates that the dysregulation of arginase may be a primary mechanism of smoking induced vascular injury, but lends further support to the coupling of Ox-LDL and activation of Arginase. Hence downstream Arginase activation may be a critical target in smoke induced vascular injury.