title: Vasoprotective effects of urocortin 1 against atherosclerosis in vitro and in vivo.
abstract: OBJECTIVE
  Atherosclerosis is the complex lesion that consists of endothelial inflammation, macrophage foam cell formation, vascular smooth muscle cell (VSMC) migration and proliferation, and extracellular matrix production. Human urocortin 1 (Ucn1), a 40-amino acid peptide member of the corticotrophin-releasing factor/urotensin I family, has potent cardiovascular protective effects. This peptide induces potent and long-lasting hypotension and coronary vasodilation. However, the relationship of Ucn1 with atherosclerosis remains unclear. The present study was performed to clarify the effects of Ucn1 on atherosclerosis.
  
  
  METHODS
  We assessed the effects of Ucn1 on the inflammatory response and proliferation of human endothelial cells (ECs), human macrophage foam cell formation, migration and proliferation of human VSMCs, extracellular matrix expression in VSMCs, and the development of atherosclerosis in apolipoprotein E-deficient (Apoe-/-) mice.
  
  
  RESULTS
  Ucn1 significantly suppressed cell proliferation without inducing apoptosis, and lipopolysaccharide-induced up-regulation of monocyte chemoattractant protein-1 and intercellular adhesion molecule-1 in human ECs. Ucn1 significantly reduced oxidized low-density lipoprotein-induced foam cell formation with a significant down-regulation of CD36 and acyl-CoA:cholesterol acyltransferase 1 in human monocyte-derived macrophages. Ucn1 significantly suppressed the migration and proliferation of human VSMCs and increased the activities of matrix metalloproteinase-2 (MMP2) and MMP9 in human VSMCs. Intraperitoneal injection of Ucn1 into Apoe-/- mice for 4 weeks significantly retarded the development of aortic atherosclerotic lesions.
  
  
  CONCLUSIONS
  This study provided the first evidence that Ucn1 prevents the development of atherosclerosis by suppressing EC inflammatory response and proliferation, macrophage foam cell formation, and VSMC migration and proliferation. Thus, Ucn1 could serve as a novel therapeutic target for atherosclerotic cardiovascular diseases.
authors.affiliation: Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Hasegawa
authors.affiliation: Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Sato
authors.affiliation: Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
authors.forename: Remina
authors.initials: R
authors.lastname: Shirai
authors.affiliation: Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
authors.forename: Rena
authors.initials: R
authors.lastname: Watanabe
authors.affiliation: Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
authors.forename: Keigo
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
authors.forename: Kaho
authors.initials: K
authors.lastname: Watanabe
authors.affiliation: Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Tokyo, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Nohtomi
authors.affiliation: Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Tokyo, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Hirano
authors.affiliation: Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Watanabe
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism / Q000503:physiopathology*; D001835:Body Weight; D018955:CD36 Antigens / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D007022:Hypotension / Q000378:metabolism; D007249:Inflammation; D008264:Macrophages / Q000166:cytology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009000:Monocytes / Q000166:cytology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D054832:Urocortins / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects
chemical_list: D001057:Apolipoproteins E; D018955:CD36 Antigens; C576814:UCN protein, human; D054832:Urocortins; D002784:Cholesterol; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9