title: Interplay between brain stem angiotensins and monocyte chemoattractant protein-1 as a novel mechanism for pressor response after ischemic stroke.
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.
authors.affiliation: 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: aywchang@mail.ncku.edu.tw.
authors.forename: Alice Y W
authors.initials: AY
authors.lastname: Chang
authors.affiliation: Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan, ROC.
authors.forename: Faith C H
authors.initials: FC
authors.lastname: Li
authors.affiliation: Department of Biological Science, National Sun Yat-sen University, Kaohsiung, Taiwan, ROC; Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan, ROC.
authors.forename: Chi-Wei
authors.initials: CW
authors.lastname: Huang
authors.affiliation: Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan, ROC.
authors.forename: Julie C C
authors.initials: JC
authors.lastname: Wu
authors.affiliation: Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan, ROC.
authors.forename: Kuang-Yu
authors.initials: KY
authors.lastname: Dai
authors.affiliation: Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan, ROC.
authors.forename: Chang-Han
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Department of Hematology and Oncology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan, ROC.
authors.forename: Shau-Hsuan
authors.initials: SH
authors.lastname: Li
authors.affiliation: Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan, ROC.
authors.forename: Chia-Hao
authors.initials: CH
authors.lastname: Su
authors.affiliation: Department of Orthopedics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan, ROC.
authors.forename: Re-Wen
authors.initials: RW
authors.lastname: Wu
mesh_terms: D000704:Analysis of Variance; D000809:Angiotensins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D002545:Brain Ischemia / Q000150:complications; D001933:Brain Stem / Q000378:metabolism*; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000502:physiology*; D006339:Heart Rate / Q000502:physiology; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009460:Neurologic Examination; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000209:etiology / Q000378:metabolism / Q000473:pathology*
chemical_list: D000809:Angiotensins; D018932:Chemokine CCL2; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger
keywords: Aliskiren; Angiotensin isoforms and receptors; Ischemic stroke; Middle cerebral artery occlusion; Monocyte chemoattractant protein-1; Neuroinflammation; Pressor response after stroke; Rostral ventrolateral medulla