Angiotensin-(1-7) counteracts the effects of Ang II on vascular smooth muscle cells, vascular remodeling and hemorrhagic stroke: Role of the NFκB inflammatory pathway

Angiotensin (Ang)-(1-7) is a potential vasoprotective peptide. In the present study, we investigated its counteractive effects to Ang II on vascular smooth muscle cells (VSMCs) and intracerebral hemorrhagic stroke (ICH) through inflammatory mechanism. In in vitro experiments, human brain VSMCs (HBVSMCs) were treated with vehicle, Ang II, Ang II + Ang-(1-7), Ang II + A-779 or Ang II + Ang-(1-7) + A-779 (Mas receptor antagonist). HBVSMC proliferation, migration and apoptosis were determined by methyl thiazolyltetrazolium, wound healing assay and flow cytometry, respectively. In in vivo experiments, C57BL/6 mice were divided into vehicle, Ang II, Ang II + Ang-(1-7), Ang II + A-779 or Ang II + Ang-(1-7) + A-779 groups before they were subjected to collagenase-induced ICH or sham surgery. Hemorrhage volume and middle cerebral artery (MCA) remodeling were determined by histological analyses. Levels of NF kappa B, inhibitor of kappa B alpha (I kappa B alpha), tumor necrosis factor-alpha (TNF-alpha), monocyte chemoattractant protein I (MCP-1) and interleukin (IL-8) were measured by western blot or ELISA. We found that 1) Ang II increased HBVSMC migration, proliferation and apoptosis, and increased the blood pressure (BP), neurological deficit score, MCA remodeling and hemorrhage volume in ICH mice. 2) Ang(1-7) counteracted these effects of Ang II, which was independent of BP, with the down-regulation of NF kappa B, up-regulation of I kappa B alpha, and decreased levels of TNF-alpha, MCP-1 and IL-8. 3) The beneficial effects of Ang-(1-7) could be abolished by A-779. In conclusion, Ang-(1-7) counteracts the effects of Ang II on ICH via modulating NF kappa B inflammation pathway in HBVSMCs and cerebral microvessels. (C) 2015 Elsevier Inc. All rights reserved.