title: Loss of smooth muscle cell disintegrin and metalloproteinase 17 transiently suppresses angiotensin II-induced hypertension and end-organ damage.
abstract: Hypertension is associated with hypertrophy and hyperplasia of smooth muscle cells (SMCs). Disintegrin and metalloproteinase 17 (ADAM17) is a membrane-bound enzyme reported to mediate SMC hypertrophy through activation of epidermal growth factor receptor (EGFR). We investigated the role of ADAM17 in Ang II-induced hypertension and end-organ damage. VSMC was isolated from mice with intact ADAM17 expression (Adam17f/f) or lacking ADAM17 in the SMC (Adam17f/f/CreSm22). Human VSMCs were isolated from the aorta of donors, and ADAM17 deletion was achieved by siRNA transfection. Ang II suppressed proliferation and migration of Adam17-deficient SMCs, but did not affect apoptosis (mouse and human), this was associated with reduced activation of EGFR and Erk1/2 signaling. Adam17f/f/CreSm22and littermate Adam17f/fmice received saline or Ang II (Alzet pumps, 1.5mg/kg/d; 2 or 4weeks). Daily blood pressure measurement in conscious mice (telemetry) showed suppressed hypertension in Adam17f/f/CreSm22mice during the first week of Ang II infusion, but by the second week, it become comparable to that in Adam17f/fmice. EGFR activation remained suppressed in Adam17f/f/CreSm22-Ang II arteries. Ex vivo vascular function and compliance assessed in mesenteric arteries were comparable between genotypes. Consistent with the transient protection against Ang II-induced hypertension, Adam17f/f/CreSm22mice exhibited significantly lower cardiac hypertrophy and fibrosis, and renal fibrosis at 2weeks post-Ang II, however this protection was abolished by the fourth week of Ang II infusion. In conclusion, while Adam17-deficiency suppresses Ang II-induced SMC remodeling in vitro, in vivo Adam17-deficiency provides only a transient protective effect against Ang II-mediated hypertension and end-organ damage.
authors.affiliation: Department of Physiology, University of Alberta, Edmonton, Alberta, Canada; Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Mengcheng
authors.initials: M
authors.lastname: Shen
authors.affiliation: Department of Physiology, University of Alberta, Edmonton, Alberta, Canada; Department of Obstetrics and Gynecology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada; Women and Children's Health Research Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Jude
authors.initials: J
authors.lastname: Morton
authors.affiliation: Department of Physiology, University of Alberta, Edmonton, Alberta, Canada; Department of Obstetrics and Gynecology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada; Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada; Women and Children's Health Research Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Sandra T
authors.initials: ST
authors.lastname: Davidge
authors.affiliation: Department of Physiology, University of Alberta, Edmonton, Alberta, Canada; Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada. Electronic address: z.kassiri@ualberta.ca.
authors.forename: Zamaneh
authors.initials: Z
authors.lastname: Kassiri
mesh_terms: D000804:Angiotensin II / Q000009:adverse effects / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D019483:Disintegrins / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D053515:Matrix Metalloproteinase 17 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*
chemical_list: D019483:Disintegrins; D000804:Angiotensin II; D066246:ErbB Receptors; D053515:Matrix Metalloproteinase 17
keywords: A disintegrin and metalloproteinase 17 (ADAM17); Blood pressure; Cardiac hypertrophy; Fibrosis; Smooth muscle cells (SMCs)