Abstract 422: Lox-1 Receptor Contributes to Oxldl-dependent Arginase Activation Through Rho-Dependent Mechanism
Oxidized LDL increases arginase activity and reciprocally decreases endothelial NO production.Inhibition of arginase II attenuates cholesterol-mediated atherogenesis through by recoupling NOS3, improving endothelialfunction and vascular stiffness. We used the specific blocking antibody (JTX92) to test whether the LOX-1 receptor expressed on endothelial cells mediates OxLDL-induced increases in arginase activity. Arginase activation by OxLDL was attenuated following preincubation of JTX92. This also prevented the dissociation of arginase into the tubulin soluble fraction. OxLDL induced Rho activation through its translocation to the membrane which was significantly inhibited by pretreatment of Simvastatin or JTX92. Furthermore, Simvastatin and Lovastatin preincubation prevented the increase in OxLDL-induced arginase activity. In addition, transfection of siRNA against RhoA/B/C reduced total RhoA protein amount and was associated with inhibition of OxLDL-stimulated arginase activitvation in endothelial cells. OxLDL induced RhoA activation (as early as 3 minutes) but, ROCK, one of the RhoA effectors, inhibition with Y27632 resulted in significant decrease in arginase activity. Simvastatin preincubation blocked OxLDL-induced dissociation of arginase from microtubule and also prevented depolymerization of tubulin. Compared to WT mice, LOX-1 mice fed a high cholesterol diet had no increase in aortic arginase activity. Furthermore, OxLDL stimulation failed to increase ROS and decrease NO production. In addition, endothelium-dependent vasorelaxation to acethylcholine was not significantly attenuated in high cholesterol fed LOX-1 mice. We conclude that LOX-1 receptor plays a key role in rho A-dependent arginase activation in OxLDL-stimulated endothelial cells and represents a critical mechanism for OxLDL mediated endothelial dysfunction Furthermore inhibition of arginase activation represents another mechanism that explains the pleotropic effects of statins.
This research has received full or partial funding support from the American Heart Association, AHA Mid-Atlantic Affiliate (Maryland, North Carolina, South Carolina, Virginia & Washington, DC).