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Deletion of multidrug resistance-associated protein 1 improves endothelial function and attenuates atherosclerosis in MRP1-/- LDL-/- double knockout mice
J. Jehle1
,
C.F.H. Mueller1
,
A. Aksoy1
,
S. Zimmer1
,
G. Nickenig1
,
V. Tiyerili1
,
1University Hospital Bonn, Department of Cardiology - Bonn - Germany
,
Background: Multidrug resistance-associated protein 1 (MRP1) is an anion transporter which is implicated in the efflux of the intracellular antioxidant anion glutathione (GSH), as well as leukotrienes (LT). Pharmacological inhibition of MRP1 exhibits antioxidative and antiatherosclerotic 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.
Methods: We crossed atherosclerosis-prone LDL−/− mice and MRP1−/− mice of FVB origin to generate MRP1−/− LDL−/− double knockout mice. These mice were fed a high-fat and cholesterol-rich diet for 7 weeks. Hereafter, 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. GSH and LTC4 levels were measured in murine plasma and aortic tissue by fluorometric assays.
Results: Arterial blood pressure was significantly reduced in MRP1−/− LDL−/− double knockout mice compared to single knockout controls (SBP: 93±5 mmHg vs. 128±4 mmHg; p<0.001; DBP: 56±3 mmHg vs. 84±3 mmHg; p<0.001). Furthermore, endothelium-dependent vasodilation of MRP1−/− LDL−/− double knockout mice yielded 44% and was significantly improved compared to MRP1-competent LDL−/− single knockout mice which yielded 22% (p<0.05). 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; p<0.05). Moreover, the atherosclerotic plaque burden of MRP1−/− LDL−/− double knockout mice was significantly diminished (0.06±0.01 vs. 0.12±0.02; p<0.05). Finally, the ratio of aortic to plasma GSH levels was markedly increased in MRP-1−/− LDL−/− double knockout mice (96±21 vs. 49±10; p=0.08) and aortic LTC4 levels were significantly decreased (725±159 pg/mg protein vs. 1480±145 pg/mg protein; p<0.01).
Conclusion: MRP1 appears to disturb cellular redox balance since its genetic disruption reduces arterial blood pressure and vascular oxidative stress in vivo. Impairment of MRP-1 action leads to an 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.
In line with the ESC mission, newly presented content is made available to all for a limited time (4 months for ESC Congress, 3 months for other events). ESC Professional Members, Association Members (Ivory & above) benefit from year-round access to all the resources from their respective Association, and to all content from previous years. Fellows of the ESC (FESC), and Professionals in training or under 40 years old, who subscribed to a Young Combined Membership package benefit from access to all ESC 365 content from all events, all editions, all year long. Find out more about ESC Memberships here.
