Genetic disruption of multidrug resistance-associated protein 1 improves endothelial function and attenuates atherosclerosis in MRP1–/– LDLr–/–double knockout mice
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Submission date: 2016-07-13
Final revision date: 2016-11-21
Acceptance date: 2016-12-08
Online publication date: 2017-06-12
Publication date: 2017-06-08
Arch Med Sci 2017;13(4):930-936
Introduction: Multidrug resistance-associated protein 1 (MRP1) is an anion transporter which is implicated in the efflux of the intracellular antioxidant anion glutathione as well as leukotrienes. Pharmacological inhibition of MRP1 exhibits antioxidative and anti atherosclerotic effects both in vitro and in vivo. However, pharmacological inhibitors of MRP1 lack selectivity, which prompted us to study the in vivo impact of a genetic disruption of MRP1 on endothelial dysfunction, reactive oxygen species formation and atherogenesis in an atherosclerotic mouse model.
Material and methods: MRP1–/– LDLr–/–double knockout mice. were fed a high-fat and cholesterol-rich diet for 7 weeks. Thereafter, endothelial function was assessed in isolated aortic rings. Reactive oxygen species were quantified by L-012 chemiluminescence, and the atherosclerotic plaque burden was measured following oil red O staining.
Results: Endothelium-dependent vasodilation of MRP1–/– LDLr–/–double knockout mice was significantly improved compared to MRP1-competent LDLr–/–single knockout mice (0.56 ±0.06 vs. 0.78 ±0.08; n = 10; p = 0.048). This improvement was accompanied by a significant reduction in reactive oxygen species formation within the aortic tissue (102 ±27 RLU/s/mg vs. 315 ±78 RLU/s/mg, n = 9–11, p = 0.03). Moreover, the atherosclerotic plaque burden of MRP1–/– LDLr–/–double knockout mice was significantly reduced (0.06 ±0.01 vs. 0.12 ±0.02; n = 6; p = 0.047). Finally, arterial blood pressure was significantly reduced in MRP1–/– LDLr–/–double knockout mice (93 ±5 mm Hg vs. 128 ±4 mm Hg; n = 8–12; p < 0.001).
Conclusions: Genetic disruption of MRP1 appears to reduce blood pressure and vascular oxidative stress in vivo, which leads to improved endothelial function and a reduced plaque burden in atherosclerotic mice. Therefore, MRP1 might represent a promising therapeutic target to improve endothelial function in patients suffering from atherosclerosis.
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