2. Academic Validation
  3. Interplay between brain stem angiotensins and monocyte chemoattractant protein-1 as a novel mechanism for pressor response after ischemic stroke

Interplay between brain stem angiotensins and monocyte chemoattractant protein-1 as a novel mechanism for pressor response after ischemic stroke

  • Neurobiol Dis. 2014 Nov;71:292-304. doi: 10.1016/j.nbd.2014.08.005.
Alice Y W Chang 1,  Faith C H Li 2,  Chi-Wei Huang 3,  Julie C C Wu 2,  Kuang-Yu Dai 2,  Chang-Han Chen 2,  Shau-Hsuan Li 4,  Chia-Hao Su 2,  Re-Wen Wu 5
Affiliations

Affiliations

  • 1 Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan, ROC; Department of Physiology, National Cheng Kung University, Tainan, Taiwan, ROC; Department of Pharmacology, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC; Department of Biological Science, National Sun Yat-sen University, Kaohsiung, Taiwan, ROC. Electronic address: [email protected].
  • 2 Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan, ROC.
  • 3 Department of Biological Science, National Sun Yat-sen University, Kaohsiung, Taiwan, ROC; Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan, ROC.
  • 4 Department of Hematology and Oncology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan, ROC.
  • 5 Department of Orthopedics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan, ROC.
PMID: 25131447 DOI: 10.1016/j.nbd.2014.08.005
Abstract

Pressor response after stroke commonly leads to early death or susceptibility to stroke recurrence, and detailed mechanisms are still lacking. We assessed the hypothesis that the renin-angiotensin system contributes to pressor response after stroke by differential modulation of the pro-inflammatory chemokine monocyte chemoattractant protein-1 (MCP-1) in the rostral ventrolateral medulla (RVLM), a key brain stem site that maintains blood pressure. We also investigated the beneficial effects of a novel Renin Inhibitor, aliskiren, against stroke-elicited pressor response. Experiments were performed in male adult Sprague-Dawley rats. Stroke induced by middle cerebral artery occlusion elicited significant pressor response, accompanied by activation of angiotensin II (Ang II)/type I receptor (AT1R) and AT2R signaling, depression of Ang-(1-7)/MasR and Ang IV/AT4R cascade, alongside augmentation of MCP-1/C-C Chemokine Receptor 2 (CCR2) signaling and neuroinflammation in the RVLM. Stroke-elicited pressor response was significantly blunted by antagonism of AT1R, AT2R or MCP-1/CCR2 signaling, and eliminated by applying Ang-(1-7) or Ang IV into the RVLM. Furthermore, stroke-activated MCP-1/CCR2 signaling was enhanced by AT1R and AT2R activation, and depressed by Ang-(1-7)/MasR and Ang IV/AT4R cascade. Aliskiren inhibited stroke-elicited pressor response via downregulating MCP-1/CCR2 activity and reduced neuroinflammation in the RVLM; these effects were potentiated by Ang-(1-7) or Ang IV. We conclude that whereas Ang II/AT1R or Ang II/AT2R signaling in the brain stem enhances, Ang-(1-7)/MasR or Ang IV/AT4R antagonizes pressor response after stroke by differential modulations of MCP-1 in the RVLM. Furthermore, combined administration of aliskiren and Ang-(1-7) or Ang IV into the brain stem provides more effective amelioration of stroked-induced pressor response.

Keywords

Aliskiren; Angiotensin isoforms and receptors; Ischemic stroke; Middle cerebral artery occlusion; Monocyte chemoattractant protein-1; Neuroinflammation; Pressor response after stroke; Rostral ventrolateral medulla.

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