Abstract 156: The Multidrug Resistance Protein 1 (MRP1) - A Mediator of Leukotriene Export in Vascular Cells
Oxidative stress has been connected with endothelial dysfunction, apoptosis and plaque development in the vasculature. MRP1 is among a family of nine currently known MRP proteins. MRP1 has previously been connected with oxidative stress management in Human Aortic Endothelial Cells (HAEC′s). Inhibition of MRP1 by MK571, a specific pharmacologic inhibitor, or downregulation by siRNA both efficiently enhanced the intracellular redox-potential and decreased the rate of apoptosis under ROS-exposure in HAEC′s. The aim of this study was to investigate the role of MRP1 as a transporter of leukotrienes, its role in mediating inflammation and its role in the setting of atherosclerosis. Vascular smooth muscle cells (VSMC) were stimulated with Angiotensin II (10−6) to induce oxidative stress over a time course up to 24 hours. Expression of MRP1 was analysed by western blot. MRP1 was not only expressed in VSMC but also upregulated in a dose dependent manner indicating an important role in the setting of cellular oxidative stress management. DCF fluorescence measurements revealed that pharmacologic inhibition of MRP1 resulted in a reduced rate of ROS production under stimulation with Angiotensin II. These results were confirmed by using MRP−/ − cells. Investigation of leukotriene export showed significantly reduced rates of leukotriene release in cells lacking MRP1. To investigate the relevance of these findings in vivo three groups of ApoE−/ −mice (n=6/group), an animal model of rapid atherosclerotic lesion development, received Western diet for 5 weeks. Additionally one group was treated with MK 571, another group was treated with Montelukast, a leukotriene-receptor antagonist. Blocking of MRP1 as well as treatment with montelukast resulted in a reduction of atherosclerotic plaques area by 50%. Both goups showed a significantly improved endothelial function compared to the control group. These findings were supported by a reduction in superoxide-production of more than 50%. Our results indicate a strong connection between MRP1, vascular function and atherogenesis. MRP1 may provide a potentially new therapeutic target for the treatment of endothelial dysfunction and atherosclerosis.