title: Vascular induction of a disintegrin and metalloprotease 17 by angiotensin II through hypoxia inducible factor 1α.
abstract: BACKGROUND
  A disintegrin and metalloprotease 17 (ADAM17) is a membrane-spanning metalloprotease overexpressed in various cardiovascular diseases such as hypertension and atherosclerosis. However, little is known regarding the regulation of ADAM17 expression in the cardiovascular system. Here, we test our hypothesis that angiotensin II induces ADAM17 expression in the vasculature.
  
  
  METHODS
  Cultured vascular smooth muscle cells were stimulated with 100 nM angiotensin II. Mice were infused with 1 μg/kg/minute angiotensin II for 2 weeks. ADAM17 expression was evaluated by a promoter-reporter construct, quantitative polymerase chain reaction, immunoblotting, and immunohistochemistry.
  
  
  RESULTS
  In vascular smooth muscle cells, angiotensin II increased ADAM17 protein expression, mRNA, and promoter activity. We determined that the angiotensin II response involves hypoxia inducible factor 1α and a hypoxia responsive element. In angiotensin II-infused mice, marked induction of ADAM17 and hypoxia inducible factor 1α was seen in vasculatures in heart and kidney, as well as in aortae, by immunohistochemistry.
  
  
  CONCLUSIONS
  Angiotensin II induces ADAM17 expression in the vasculatures through a hypoxia inducible factor 1α-dependent transcriptional upregulation, potentially contributing to end-organ damage in the cardiovascular system.
authors.affiliation: Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, Pennsylvania;
authors.forename: Takashi
authors.initials: T
authors.lastname: Obama
authors.affiliation: Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, Pennsylvania;
authors.forename: Takehiko
authors.initials: T
authors.lastname: Takayanagi
authors.affiliation: Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, Pennsylvania;
authors.forename: Tomonori
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, Pennsylvania;
authors.forename: Allison M
authors.initials: AM
authors.lastname: Bourne
authors.affiliation: Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, Pennsylvania;
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Elliott
authors.affiliation: Immunology Division, Department of Pediatrics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
authors.forename: Martine
authors.initials: M
authors.lastname: Charbonneau
authors.affiliation: Immunology Division, Department of Pediatrics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
authors.forename: Claire M
authors.initials: CM
authors.lastname: Dubois
authors.affiliation: Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, Pennsylvania; seguchi@temple.edu.
authors.forename: Satoru
authors.initials: S
authors.lastname: Eguchi
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072198:ADAM17 Protein; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology; D032389:Myocytes, Smooth Muscle; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D015854:Up-Regulation
chemical_list: C497443:Hif1a protein, mouse; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D000804:Angiotensin II; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse; C000606464:Adam17 protein, rat
keywords: blood pressure; epidermal growth factor receptor; hypertension; renin–angiotensin system; signal transduction; tumor necrosis factor α converting enzyme; vascular biology.