RRC ID 11802
Author Inaba S, Iwai M, Tomono Y, Senba I, Furuno M, Kanno H, Okayama H, Mogi M, Higaki J, Horiuchi M.
Title Exaggeration of focal cerebral ischemia in transgenic mice carrying human Renin and human angiotensinogen genes.
Journal Stroke
Abstract BACKGROUND AND PURPOSE: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.
Volume 40(2)
Pages 597-603
Published 2009-2-1
DOI 10.1161/STROKEAHA.108.519801
PII STROKEAHA.108.519801
PMID 19023100
MeSH Angiotensin II / metabolism Angiotensin II Type 1 Receptor Blockers / pharmacology Angiotensin II Type 1 Receptor Blockers / therapeutic use Angiotensinogen / genetics* Animals Brain Chemistry / genetics Brain Chemistry / physiology Brain Ischemia / drug therapy Brain Ischemia / genetics* Brain Ischemia / pathology* Capillaries / pathology Cerebrovascular Circulation Humans Infarction, Middle Cerebral Artery / pathology Male Mice Mice, Transgenic Oxidative Stress / physiology Receptor, Angiotensin, Type 1 / biosynthesis Receptor, Angiotensin, Type 1 / genetics Receptor, Angiotensin, Type 2 / biosynthesis Receptor, Angiotensin, Type 2 / genetics Renin / genetics* Reverse Transcriptase Polymerase Chain Reaction Superoxides / metabolism Tetrazoles / pharmacology Valine / analogs & derivatives Valine / pharmacology Valsartan
IF 7.19
Times Cited 38
Mice RBRC01122 RBRC01123