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(Stroke. 2008;39:2554.)
© 2008 American Heart Association, Inc.

Original Contributions

Deletion of Angiotensin II Type 2 Receptor Attenuates Protective Effects of Bone Marrow Stromal Cell Treatment on Ischemia–Reperfusion Brain Injury in Mice

Jun Iwanami, MS; Masaki Mogi, MD, PhD; Jian-Mei Li, MD, PhD; Kana Tsukuda, BS; Li-Juan Min, MD, PhD; Akiko Sakata, MD; Teppei Fujita, MD; Masaru Iwai, MD, PhD Masatsugu Horiuchi, MD, PhD

From the Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Graduate School of Medicine, Tohon, 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— Protective effects of bone marrow stromal cells (MSCs) on ischemic brain damage have been highlighted. We examined the possibility that deletion of AT₂ receptor could attenuate the cerebroprotective effects of MSC using AT₂ receptor-deficient mice (Agtr2^–) and the effect of selective AT₁ 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- 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- 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 AT₁ receptor blocker, valsartan, significantly improved survival rates in Agtr2^–-MSC-injected mice.

Conclusions— These results suggest that AT₂ receptor signaling in MSC attenuated brain damage and neurological deficit (deleted).

Supplemental Materials and Methods