title: Exaggeration of focal cerebral ischemia in transgenic mice carrying human Renin and human angiotensinogen genes.
abstract: OBJECTIVE
  We examined the possibility that activation of the human brain renin-angiotensin system is involved in enhancement of ischemic brain damage using chimeric transgenic mice with human renin (hRN) and human angiotensinogen (hANG) genes.
  
  
  METHODS
  Chimeric (hRN/hANG-Tg) mice were generated by mating of hRN and hANG transgenic mice. Permanent occlusion of the middle cerebral artery (MCA) by an intraluminal filament technique induced focal ischemic brain lesions.
  
  
  RESULTS
  hRN/hANG-Tg mice showed higher angiotensin II levels in the plasma and brain. The ischemic brain area at 24 hours after MCA occlusion was significantly enlarged in hRN/hANG-Tg mice with an enhanced neurological deficit compared to that in wild-type, hRN-Tg and hANG-Tg mice. The reduction of cerebral blood flow in the periphery region of the MCA territory after MCA occlusion was markedly exaggerated in hRN/hANG-Tg mice. Superoxide anion production in the brain and arteries was also increased significantly in hRN/hANG-Tg mice even before MCA occlusion and was further enhanced after MCA occlusion. Treatment with an AT(1) receptor blocker, valsartan (3.0 mg/kg per day), for 2 weeks significantly reduced the ischemic brain area and improved the neurological deficit after MCA occlusion in hRN/hANG-Tg mice, similar to those in wild-type, hRN-Tg, and hANG-Tg mice, with restoration of cerebral blood flow in the peripheral region and decreases in superoxide anion production and blood pressure.
  
  
  CONCLUSIONS
  These results indicate that activation of the human renin-angiotensin system exaggerates ischemic brain damage mainly through stimulation of the AT(1) receptor and marked reduction of cerebral blood flow and enhanced oxidative stress.
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Shitsukawa, Tohon, Ehime, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Inaba
authors.forename: Masaru
authors.initials: M
authors.lastname: Iwai
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Tomono
authors.forename: Izumi
authors.initials: I
authors.lastname: Senba
authors.forename: Megumi
authors.initials: M
authors.lastname: Furuno
authors.forename: Harumi
authors.initials: H
authors.lastname: Kanno
authors.forename: Hideki
authors.initials: H
authors.lastname: Okayama
authors.forename: Masaki
authors.initials: M
authors.lastname: Mogi
authors.forename: Jitsuo
authors.initials: J
authors.lastname: Higaki
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Horiuchi
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use; D000808:Angiotensinogen / Q000235:genetics*; D000818:Animals; D001923:Brain Chemistry / Q000235:genetics / Q000502:physiology; D002545:Brain Ischemia / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D002196:Capillaries / Q000473:pathology; D002560:Cerebrovascular Circulation; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018384:Oxidative Stress / Q000502:physiology; D044140:Receptor, Angiotensin, Type 1 / Q000096:biosynthesis / Q000235:genetics; D044139:Receptor, Angiotensin, Type 2 / Q000096:biosynthesis / Q000235:genetics; D012083:Renin / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013481:Superoxides / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; D000808:Angiotensinogen; D013481:Superoxides; D000804:Angiotensin II; D000068756:Valsartan; D012083:Renin; D014633:Valine