ウロテンシン2の動脈硬化促進作用とUT受容体拮抗剤4-aminoquinolineの抗動脈硬化作用

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Our recent studies indicate that urotensin II (UII), the most potent vasoconstrictor peptide identified to date, potentiates human macrophage foam cell formation and vascular smooth muscle cell proliferation, and UII levels are increased in the plasma of hypertensive patients with carotid atherosclerotic plaques. Here, we investigated the enhancing effect of UII on atherosclerosis in apolipoprotein E (apoE) - deficient mice and its suppression by 4-aminoquinoline, a non-peptide UII receptor (UT) -selective antagonist. UII, UII + 4-aminoquinoline, or vehicle was infused for 4 weeks through an osmotic mini-pump into 9-week-old apoE-deficient mice on a high-fat diet. Aortic atherosclerosis and foam cell formation in exudate peritoneal macrophages were examined. Atherosclerotic lesions as well as plasma levels of UII, reactive oxygen species (ROS), and oxidized low-density lipoprotein (oxLDL) and oxLDL-induced foam cell formation were significantly greater in UII-infused mice than in the vehicle-infused controls. Western blotting analysis showed increased expressions of scavenger receptors (CD36 and SR-A) and acyl-CoA: cholesterol acyltransferase 1 (ACATI) in these macrophages. Increases in these parameters were significantly reduced by addition of 4-aminoquinoline. In apoE-deficient mice even without UII infusion, the treatment with 4-aminoquinoline for 8 weeks significantly prevented the development of atherosclerotic lesions. Our results suggest that an increased plasma UII level stimulates oxLDL and ROS production and macrophage foam cell formation via increased expressions of CD36, SR-A, and ACAT1, contributing to the development of atherosclerosis in apoE-deficient mice. UT antagonism may provide a therapeutic strategy against atherosclerosis.

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