Multidrug Resistance Protein-1 Affects Oxidative Stress, Endothelial Dysfunction, and Atherogenesis via Leukotriene C ₄ Export

<jats:p> <jats:bold> <jats:italic>Background—</jats:italic> </jats:bold> We recently showed that the multidrug resistance related protein-1 (MRP1) is important for the management of oxidative stress in vascular cells. However, the underlying mechanism and the in vivo relevance of these findings remain elusive. We hypothesize that inside-outside transport of leukotriene C <jats:sub>4</jats:sub> (LTC <jats:sub>4</jats:sub> ) via MRP1 is a substantial proatherogenic mechanism in the vasculature. To test this hypothesis, we investigated the effects of MRP1 inhibition and LTC <jats:sub>4</jats:sub> receptor blockade (Cys-LT1 receptor) in vitro and in vivo. </jats:p> <jats:p> <jats:bold> <jats:italic>Methods and Results—</jats:italic> </jats:bold> MRP1 is expressed abundantly in vascular smooth muscle cells (VSMCs). Pharmacological inhibition of MRP1 via MK571 reduces angiotensin II–induced reactive oxygen species release by 59% (L012 fluorescence) in VSMCs. The release of reactive oxygen species after angiotensin II stimulation also is inhibited by blockade of the Cys-LT1 receptor with montelukast. Incubation of VSMCs with recombined LTC <jats:sub>4</jats:sub> causes enhanced rates of reactive oxygen species and proliferation in wild-type and MRP1 <jats:sup>−/−</jats:sup> VSMCs. Accordingly, the LTC <jats:sub>4</jats:sub> release in the cell culture supernatant of MRP1 <jats:sup>−/−</jats:sup> VSMCs is significantly decreased compared with wild-type cells. To extend our observations to the in vivo situation, atherosclerosis-prone apolipoprotein E–deficient mice on a high-cholesterol diet were treated with placebo, the MRP1 inhibitor MK571, or the Cys-LT1 receptor inhibitor montelukast for 6 weeks. Treatment with MK571 or montelukast reduced vascular reactive oxygen species production, significantly improved endothelial function, and ameliorated atherosclerotic plaque generation by 52% and 61%, respectively. </jats:p> <jats:p> <jats:bold> <jats:italic>Conclusions—</jats:italic> </jats:bold> These findings indicate that MRP1 and LTC <jats:sub>4</jats:sub> exert proatherosclerotic effects and that both MRP1 and LTC <jats:sub>4</jats:sub> are potentially promising targets for atheroprotective therapy. </jats:p>