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(Stroke. 2009;40:597.)
© 2009 American Heart Association, Inc.

Original Contributions

Exaggeration of Focal Cerebral Ischemia in Transgenic Mice Carrying Human Renin and Human Angiotensinogen Genes

Shinji Inaba, MD; Masaru Iwai, MD, PhD; Yumiko Tomono, BS; Izumi Senba, MT; Megumi Furuno, MT; Harumi Kanno, MA; Hideki Okayama, MD, PhD; Masaki Mogi, MD, PhD; Jitsuo Higaki, MD, PhD Masatsugu Horiuchi, MD, PhD

From the Departments of Molecular Cardiovascular Biology and Pharmacology (S.I., M.I., Y.T., I.S., M.F., H.K., M.M., M.H.) and Integrated Medicine and Informatics (S.I., H.O., J.H.), Ehime University Graduate School of Medicine, Shitsukawa, Ehime, Japan.

Correspondence to Masatsugu Horiuchi, MD, PhD, FAHA, Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Shitsukawa, Tohon, Ehime 791-0295, Japan. E-mail horiuchi{at}m.ehime-u.ac.jp

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 AT₁ 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 AT₁ receptor and marked reduction of cerebral blood flow and enhanced oxidative stress.

Key Words: angiotensin • brain infarction • hypertension • receptors

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