title: Chronic urotensin II infusion enhances macrophage foam cell formation and atherosclerosis in apolipoprotein E-knockout mice.
abstract: OBJECTIVE
  Our recent studies have indicated that urotensin II, the most potent vasoconstrictor peptide identified to date, potentiates human macrophage foam cell formation and vascular smooth muscle cell proliferation, and its levels are increased in the plasma of hypertensive patients with carotid atherosclerotic plaques. In the present study, we investigated the enhancing effect of urotensin II on atherosclerosis in apolipoprotein E-knockout mice and its suppression by 4-aminoquinoline, an urotensin II receptor-selective antagonist.
  
  
  METHODS
  Urotensin II, urotensin II + 4-aminoquinoline, or vehicle was infused for 4 weeks through an osmotic mini-pump into 9-week-old apolipoprotein E-knockout mice on a high-fat diet. Aortic atherosclerosis and foam cell formation in exudate peritoneal macrophages were examined.
  
  
  RESULTS
  Atherosclerotic lesions as well as plasma levels of urotensin II, reactive oxygen species, and oxidized low-density lipoprotein and oxidized low-density lipoprotein-induced foam cell formation were significantly greater in urotensin II-infused mice than vehicle-infused controls. Western blotting analysis showed increased expression of scavenger receptors (CD36 and scavenger receptor class A) and acyl-CoA:cholesterol acyltransferase-1 in these macrophages. Increases in these parameters were significantly reduced by addition of 4-aminoquinoline. In apolipoprotein E-knockout mice even without urotensin II infusion, the treatment with 4-aminoquinoline for 8 weeks significantly prevented the development of atherosclerotic lesions.
  
  
  CONCLUSIONS
  Our results provide the first evidence that increased plasma urotensin II level stimulates oxidized low-density lipoprotein and reactive oxygen species production and macrophage foam cell formation via increased expression of CD36, scavenger receptor class A, and acyl-CoA:cholesterol acyltransferase-1, contributing to the development of atherosclerosis in apolipoprotein E-deficient mice. Urotensin II receptor antagonism may be a promising therapeutic strategy against atherosclerosis.
authors.affiliation: First Department of Internal Medicine, Showa University School of Medicine, Tokyo, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Shiraishi
authors.forename: Takuya
authors.initials: T
authors.lastname: Watanabe
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Suguro
authors.forename: Masaharu
authors.initials: M
authors.lastname: Nagashima
authors.forename: Rina
authors.initials: R
authors.lastname: Kato
authors.forename: Shigeki
authors.initials: S
authors.lastname: Hongo
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Itabe
authors.forename: Akira
authors.initials: A
authors.lastname: Miyazaki
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Hirano
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Adachi
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000503:physiopathology*; D018955:CD36 Antigens / Q000378:metabolism; D004036:Diet, Atherogenic; D005487:Foam Cells / Q000502:physiology*; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017382:Reactive Oxygen Species / Q000378:metabolism; D051117:Scavenger Receptors, Class A / Q000378:metabolism; D002785:Sterol O-Acyltransferase / Q000378:metabolism; D014579:Urotensins / Q000502:physiology*
chemical_list: D001057:Apolipoproteins E; D018955:CD36 Antigens; D008077:Lipoproteins, LDL; D017382:Reactive Oxygen Species; D051117:Scavenger Receptors, Class A; D014579:Urotensins; C099252:oxidized low density lipoprotein; C029677:urotensin II; D002785:Sterol O-Acyltransferase; C493492:sterol O-acyltransferase 1