Liver X receptor activation attenuates plaque formation and improves vasomotor function of the aortic artery in atherosclerotic ApoE−/− mice
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The severity of atherosclerosis is primarily determined by overall lipid metabolism and the degree of inflammation present within the vessel wall. We evaluated the effects of T-0901317, a liver X receptor agonist, on the atherosclerosis process, and especially on the endothelial function in ApoE−/− mice.
Methods and results
ApoE−/− mice were treated with LXR agonist T-0901317 (1 μmol/L) for 6 weeks. ApoE−/− mice receiving T-0901317 were found to have markedly improved overall serum lipid profiles, albeit increased serum triglycerides. MRI imaging demonstrated that T-0901317 attenuated the atherosclerotic plaque burden in the aorta of ApoE−/− mice. Transmission electron microscopy and immunohistochemistry revealed attenuated ultrastructural changes as well as enhanced expression of the ATP-binding cassette transporter ABCA1. In addition, treatment with the LXR agonist improved the vasomotor function of atherosclerotic arteries, as assessed by KCl/norepinephrine-induced vasoconstrictive and acetylcholine-induced vasorelaxation functional assays. In vitro studies showed increased ABCG1, phospho-Akt and phospho-eNOS expression in ApoE−/− mice aorta endothelial cells (ECs) after T0901317 treatment.
The present study suggest that LXR agonists protect the endothelium against atherosclerotic insults by increasing ABCA1 and ABCG1 expression, and improve the endothelial-dependent vasomotor function probably by promoting Akt and eNOS phosphorylation.
KeywordsLiver X receptors (LXRs) ATP-binding cassette transporter A1 (ABCA1) Apolipoprotein E gene knockout (ApoE−/−) mice Atherosclerosis Vasomotoricity Endothelium
This work was supported by National Nature Science Foundation of China (No. 81090274, No. 81090270, No. 81100579), Innovation Team Start-up Grant by China Department of Education (2010CXTD01) and China's Ministry of Science and Technology 863 Program (2012AA02A603).
Conflict of interest
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