Multidrug resistance protein-1 affects oxidative stress, endothelial dysfunction, and atherogenesis via leukotriene C4 export.
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 C(4) (LTC(4)) via MRP1 is a substantial proatherogenic mechanism in the vasculature. To test this hypothesis, we investigated the effects of MRP1 inhibition and LTC(4) receptor blockade (Cys-LT1 receptor) in vitro and in vivo.


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 LTC(4) causes enhanced rates of reactive oxygen species and proliferation in wild-type and MRP1(-/-) VSMCs. Accordingly, the LTC(4) 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 LTC(4) exert proatherosclerotic effects and that both MRP1 and LTC(4) are potentially promising targets for atheroprotective therapy.
Mueller
Cornelius F H
CF
Medizinische Klinik und Poliklinik II, Universitätsklinikum Bonn, Sigmund Freud Str 25, 53105 Bonn, Germany. cornelius.mueller@ukb.uni-bonn.de
Wassmann
Kerstin
K
Widder
Julian D
JD
Wassmann
Sven
S
Chen
Chia Hui
CH
Keuler
Barbara
B
Kudin
Alexey
A
Kunz
Wolfram S
WS
Nickenig
Georg
G
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D050197:Atherosclerosis / Q000209:etiology*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000503:physiopathology*; D017997:Leukotriene C4 / Q000378:metabolism*; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D018384:Oxidative Stress; D021381:Protein Transport; D051381:Rats
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017997:Leukotriene C4