Loss of smooth muscle cell disintegrin and metalloproteinase 17 transiently suppresses angiotensin II-induced hypertension and end-organ damage

Mengcheng Shen; Jude Morton; Sandra T Davidge; Zamaneh Kassiri

doi:10.1016/j.yjmcc.2016.12.001

Loss of smooth muscle cell disintegrin and metalloproteinase 17 transiently suppresses angiotensin II-induced hypertension and end-organ damage

J Mol Cell Cardiol. 2017 Feb:103:11-21. doi: 10.1016/j.yjmcc.2016.12.001. Epub 2016 Dec 16.

Authors

Mengcheng Shen¹, Jude Morton², Sandra T Davidge³, Zamaneh Kassiri⁴

Affiliations

¹ Department of Physiology, University of Alberta, Edmonton, Alberta, Canada; Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
² 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.
³ 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.
⁴ 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.

PMID: 27993561
DOI: 10.1016/j.yjmcc.2016.12.001

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 (Adam17^f/f) or lacking ADAM17 in the SMC (Adam17^f/f/Cre^Sm22). 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. Adam17^f/f/Cre^Sm22 and littermate Adam17^f/f mice 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 Adam17^f/f/Cre^Sm22 mice during the first week of Ang II infusion, but by the second week, it become comparable to that in Adam17^f/f mice. EGFR activation remained suppressed in Adam17^f/f/Cre^Sm22-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, Adam17^f/f/Cre^Sm22 mice 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.

Keywords: A disintegrin and metalloproteinase 17 (ADAM17); Blood pressure; Cardiac hypertrophy; Fibrosis; Smooth muscle cells (SMCs).

MeSH terms

Angiotensin II / adverse effects
Angiotensin II / metabolism*
Animals
Apoptosis
Disease Models, Animal
Disintegrins / metabolism*
ErbB Receptors / metabolism
Humans
Hypertension / etiology*
Hypertension / metabolism*
Hypertension / pathology
Male
Matrix Metalloproteinase 17 / deficiency
Matrix Metalloproteinase 17 / genetics
Matrix Metalloproteinase 17 / metabolism*
Mice
Mice, Knockout
Muscle, Smooth, Vascular / metabolism
Myocytes, Smooth Muscle / metabolism*

Substances

Disintegrins
Angiotensin II
ErbB Receptors
Matrix Metalloproteinase 17