| First Author | Shen M | Year | 2017 |
| Journal | J Mol Cell Cardiol | Volume | 103 |
| Pages | 11-21 | PubMed ID | 27993561 |
| Mgi Jnum | J:251574 | Mgi Id | MGI:6102741 |
| Doi | 10.1016/j.yjmcc.2016.12.001 | Citation | Shen M, et al. (2017) Loss of smooth muscle cell disintegrin and metalloproteinase 17 transiently suppresses angiotensin II-induced hypertension and end-organ damage. J Mol Cell Cardiol 103:11-21 |
| abstractText | 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. |
