This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 117/22/2912    most recent CIRCULATIONAHA.107.747667v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Mueller, C. F.H. Articles by Nickenig, G. PubMed PubMed Citation Articles by Mueller, C. F.H. Articles by Nickenig, G. Related Collections Mechanism of atherosclerosis/growth factors ACE/Angiotension receptors Pathophysiology Risk Factors Growth factors/cytokines Smooth muscle proliferation and differentiation Related Article

(Circulation. 2008;117:2912-2918.)
© 2008 American Heart Association, Inc.

Molecular Cardiology

Multidrug Resistance Protein-1 Affects Oxidative Stress, Endothelial Dysfunction, and Atherogenesis via Leukotriene C₄ Export

Cornelius F.H. Mueller, MD; Kerstin Wassmann, MD; Julian D. Widder, MD; Sven Wassmann, MD; Chia Hui Chen, MD; Barbara Keuler, MS; Alexey Kudin, PhD; Wolfram S. Kunz, PhD; Georg Nickenig, MD

From Medizinische Klinik und Poliklinik II, Innere Medizin (C.F.H.M., K.W., S.W., C.H.C., B.K., G.N.) and Department of Epileptology (A.K., W.S.K.), Universitätsklinikum Bonn, Bonn, and Medizinische Klinik I, Universitätsklinikum Würzburg, Würzburg (J.W.), Germany.

Correspondence to Cornelius Mueller, Medizinische Klinik und Poliklinik II, Universitätsklinikum Bonn, Sigmund Freud Str 25, 53105 Bonn, Germany. E-mail cornelius.mueller{at}ukb.uni-bonn.de

Received October 20, 2007; accepted March 13, 2008.

Background— 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 C₄ (LTC₄) via MRP1 is a substantial proatherogenic mechanism in the vasculature. To test this hypothesis, we investigated the effects of MRP1 inhibition and LTC₄ receptor blockade (Cys-LT1 receptor) in vitro and in vivo.

Methods and Results— 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 LTC₄ causes enhanced rates of reactive oxygen species and proliferation in wild-type and MRP1^–/– VSMCs. Accordingly, the LTC₄ release in the cell culture supernatant of MRP1^–/– 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.

Conclusions— These findings indicate that MRP1 and LTC₄ exert proatherosclerotic effects and that both MRP1 and LTC₄ are potentially promising targets for atheroprotective therapy.

---

 

CLINICAL PERSPECTIVE

Related Article:

Clinical Summaries
Circulation 2008 117: 2841-2843. [Full Text]