Liver X receptor activation attenuates plaque formation and improves vasomotor function of the aortic artery in atherosclerotic ApoE(-/-) mice

Inflamm Res. 2012 Dec;61(12):1299-307. doi: 10.1007/s00011-012-0529-4. Epub 2012 Jul 26.

Abstract

Aim: 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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 1
  • ATP-Binding Cassette Transporters / metabolism
  • Animals
  • Aorta, Thoracic / drug effects*
  • Aorta, Thoracic / physiology
  • Aorta, Thoracic / ultrastructure
  • Apolipoproteins E / deficiency
  • Apolipoproteins E / genetics
  • Atherosclerosis / blood
  • Atherosclerosis / drug therapy*
  • Atherosclerosis / physiopathology
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / physiology
  • Endothelium, Vascular / ultrastructure
  • Hydrocarbons, Fluorinated / pharmacology*
  • Hydrocarbons, Fluorinated / therapeutic use
  • Lipids / blood
  • Lipoproteins / metabolism
  • Liver X Receptors
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nitric Oxide Synthase Type III / metabolism
  • Oncogene Protein v-akt / metabolism
  • Orphan Nuclear Receptors / agonists*
  • Plaque, Atherosclerotic / blood
  • Plaque, Atherosclerotic / drug therapy*
  • Plaque, Atherosclerotic / physiopathology
  • Sulfonamides / pharmacology*
  • Sulfonamides / therapeutic use
  • Vasoconstriction / drug effects
  • Vasodilation / drug effects

Substances

  • ABCG1 protein, mouse
  • ATP Binding Cassette Transporter 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 1
  • ATP-Binding Cassette Transporters
  • Apolipoproteins E
  • Hydrocarbons, Fluorinated
  • Lipids
  • Lipoproteins
  • Liver X Receptors
  • Orphan Nuclear Receptors
  • Sulfonamides
  • TO-901317
  • Nitric Oxide Synthase Type III
  • Nos3 protein, mouse
  • Oncogene Protein v-akt