title: Endothelin-1 overexpression exacerbates atherosclerosis and induces aortic aneurysms in apolipoprotein E knockout mice.
abstract: OBJECTIVE
  Endothelin (ET)-1 plays a role in vascular reactive oxygen species production and inflammation. ET-1 has been implicated in human atherosclerosis and abdominal aortic aneurysm (AAA) development. ET-1 overexpression exacerbates high-fat diet-induced atherosclerosis in apolipoprotein E(-/-) (Apoe(-/-)) mice. ET-1-induced reactive oxygen species and inflammation may contribute to atherosclerosis progression and AAA development.
  
  
  RESULTS
  Eight-week-old male wild-type mice, transgenic mice overexpressing ET-1 selectively in endothelium (eET-1), Apoe(-/-) mice, and eET-1/Apoe(-/-) mice were fed high-fat diet for 8 weeks. eET-1/Apoe(-/-) had a 45% reduction in plasma high-density lipoprotein (P<0.05) and presented ≥ 2-fold more aortic atherosclerotic lesions compared with Apoe(-/-) (P<0.01). AAAs were detected only in eET-1/Apoe(-/-) (8/21; P<0.05). Reactive oxygen species production was increased ≥ 2-fold in perivascular fat, media, or atherosclerotic lesions in the ascending aorta and AAAs of eET-1/Apoe(-/-) compared with Apoe(-/-) (P<0.05). Monocyte/macrophage infiltration was enhanced ≥ 2.5-fold in perivascular fat of ascending aorta and AAAs in eET-1/Apoe(-/-) compared with Apoe(-/-) (P<0.05). CD4(+) T cells were detected almost exclusively in perivascular fat (3/6) and atherosclerotic lesions (5/6) in ascending aorta of eET-1/Apoe(-/-) (P<0.05). The percentage of spleen proinflammatory Ly-6C(hi) monocytes was enhanced 26% by ET-1 overexpression in Apoe(-/-) (P<0.05), and matrix metalloproteinase-2 was increased 2-fold in plaques of eET-1/Apoe(-/-) (P<0.05) compared with Apoe(-/-).
  
  
  CONCLUSIONS
  ET-1 plays a role in progression of atherosclerosis and AAA formation by decreasing high-density lipoprotein, and increasing oxidative stress, inflammatory cell infiltration, and matrix metalloproteinase-2 in perivascular fat, vascular wall, and atherosclerotic lesions.
authors.affiliation: From the Lady Davis Institute for Medical Research (M.W.L., M.O.R.M., T.B., A.R., K.M., P.P., E.L.S.), Department of Medicine (E.L.S.), and Department of Oncology (K.M.), Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montréal, Québec, Canada.
authors.forename: Melissa W
authors.initials: MW
authors.lastname: Li
authors.forename: Muhammad Oneeb Rehman
authors.initials: MO
authors.lastname: Mian
authors.forename: Tlili
authors.initials: T
authors.lastname: Barhoumi
authors.forename: Asia
authors.initials: A
authors.lastname: Rehman
authors.forename: Koren
authors.initials: K
authors.lastname: Mann
authors.forename: Pierre
authors.initials: P
authors.lastname: Paradis
authors.forename: Ernesto L
authors.initials: EL
authors.lastname: Schiffrin
mesh_terms: D000273:Adipose Tissue / Q000276:immunology / Q000378:metabolism; D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D001011:Aorta / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000209:etiology / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000209:etiology / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008075:Lipoproteins, HDL / Q000097:blood; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D058226:Plaque, Atherosclerotic; D017382:Reactive Oxygen Species / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000950:Antigens, Ly; D001057:Apolipoproteins E; D019332:Endothelin-1; D008075:Lipoproteins, HDL; C494192:Ly-6C antigen, mouse; D017382:Reactive Oxygen Species; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse
keywords: T lymphocytes; cholesterol, HDL; elastin; fibronectin; inflammation; monocytes; oxidative stress