Reference - Detail
RRC ID | 11802 |
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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 |
WOS Category | CLINICAL NEUROLOGY PERIPHERAL VASCULAR DISEASE |
Resource | |
Mice | RBRC01122 RBRC01123 |