title: Deletion of angiotensin II type 2 receptor attenuates protective effects of bone marrow stromal cell treatment on ischemia-reperfusion brain injury in mice.
abstract: OBJECTIVE
  Protective effects of bone marrow stromal cells (MSCs) on ischemic brain damage have been highlighted. We examined the possibility that deletion of AT(2) receptor could attenuate the cerebroprotective effects of MSC using AT(2) receptor-deficient mice (Agtr2 (-)) and the effect of selective AT(1) receptor blocker.
  
  
  METHODS
  Wild-type mice (Agtr2 (+)) were subjected to 3 hours of focal brain ischemia followed by reperfusion (ischemia-reperfusion injury). Simultaneously, Agtr2 (+)-MSC, Agtr2 (-)-MSC, or saline was injected through the tail vein.
  
  
  RESULTS
  Survival rates at 6 days after ischemia-reperfusion injury were as follows: approximately 50% in saline-injected mice, 80% in Agtr2 (+)-MSC-injected mice, and 20% in Agtr2 (-)-MSC-injected mice. Neurological deficit after ischemia-reperfusion injury was improved in Agtr2 (+)-MSC-injected mice, but not in Agtr2 (-)-MSC-injected mice. After 48 hours of ischemia-reperfusion injury, brain infarct size was reduced in Agtr2 (+)-MSC-injected mice, but not in Agtr2 (-)-MSC-injected mice. Moreover, brain edema was significantly ameliorated in Agtr2 (+)-MSC-treated mice but not in Agtr2 (-)-MSC-treated mice. Furthermore, the increase in mRNA expression of tumor necrosis factor-alpha and monocyte chemoattractant protein-1 in the ischemic brain was less in Agtr2 (+)-MSC-treated mice in the ipsilateral site, but was similar in the contralateral hemisphere. Tumor necrosis factor-alpha level was increased in both the contralateral hemisphere and ipsilateral hemisphere of Agtr2 (-)-MSC-treated mice. In contrast, monocyte chemoattractant protein-1 levels tended to increase Agtr2 (-)-MSC-treated mice without a significant difference. Treatment of MSC with an AT(1) receptor blocker, valsartan, significantly improved survival rates in Agtr2 (-)-MSC-injected mice.
  
  
  CONCLUSIONS
  These results suggest that AT(2) receptor signaling in MSC attenuated brain damage and neurological deficit (deleted).
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Graduate School of Medicine, Shitsukawa, Tohon, Ehime 791-0295, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Iwanami
authors.forename: Masaki
authors.initials: M
authors.lastname: Mogi
authors.forename: Jian-Mei
authors.initials: JM
authors.lastname: Li
authors.forename: Kana
authors.initials: K
authors.lastname: Tsukuda
authors.forename: Li-Juan
authors.initials: LJ
authors.lastname: Min
authors.forename: Akiko
authors.initials: A
authors.lastname: Sakata
authors.forename: Teppei
authors.initials: T
authors.lastname: Fujita
authors.forename: Masaru
authors.initials: M
authors.lastname: Iwai
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Horiuchi
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D016026:Bone Marrow Transplantation / Q000379:methods*; D020520:Brain Infarction / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D002545:Brain Ischemia / Q000235:genetics / Q000503:physiopathology / Q000628:therapy; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics*; D015427:Reperfusion Injury / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D017154:Stromal Cells / Q000637:transplantation*; D015996:Survival Rate; D013777:Tetrazoles / Q000494:pharmacology; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan
chemical_list: D000959:Antihypertensive Agents; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; D014409:Tumor Necrosis Factor-alpha; D000068756:Valsartan; D014633:Valine