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J. Biol. Chem., Vol. 281, Issue 19, 13209-13216, May 12, 2006

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A Novel Function of Angiotensin II in Skin Wound Healing

INDUCTION OF FIBROBLAST AND KERATINOCYTE MIGRATION BY ANGIOTENSIN II VIA HEPARIN-BINDING EPIDERMAL GROWTH FACTOR (EGF)-LIKE GROWTH FACTOR-MEDIATED EGF RECEPTOR TRANSACTIVATION^*

Yoko Yahata¹, Yuji Shirakata¹², Sho Tokumaru, Lujun Yang, Xiuju Dai, Mikiko Tohyama, Teruko Tsuda, Koji Sayama, Masaru Iwai, Masatsugu Horiuchi, and Koji Hashimoto

From the Department of Dermatology and the Division of Medical Biochemistry and Cardiovascular Biology, Ehime University School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan

The role of angiotensin II (Ang II) in the control of systemic blood pressure and volume homeostasis is well known and has been extensively studied. Recently, Ang II was suggested to also have a function in skin wound healing. In the present study, the in vivo function of Ang II in skin wound healing was investigated using Ang II type 1 receptor (AT1R) knock-out mice. Wound healing in these mice was found to be markedly delayed. Keratinocytes and fibroblasts play important roles in wound healing, and thus the effect of Ang II on the migration of these cells was examined. Ang II stimulated keratinocyte and fibroblast migration in a dose-dependent manner. It has been reported that G protein-coupled receptor (GPCR) activation induces epidermal growth factor (EGF) receptor (EGFR) transactivation through the shedding of heparin-binding EGF-like growth factor (HB-EGF). As AT1R is a GPCR, it was hypothesized that Ang II-induced keratinocyte and fibroblast migration is mediated by EGFR transactivation. Ang II induced EGFR phosphorylation, which was inhibited by an AT1R antagonist, HB-EGF neutralizing antibody, and an HB-EGF antagonist in both keratinocytes and in fibroblasts. Moreover, Ang II-induced migration of keratinocytes and fibroblasts was also prevented by these inhibitors. Taken together, these findings clearly demonstrate, for the first time, that Ang II plays an important role in skin wound healing and that it functions by accelerating keratinocyte and fibroblast migration in a process mediated by HB-EGF shedding.

Received for publication, September 6, 2005 , and in revised form, March 16, 2006.

^* This work was supported in part by a grant for scientific research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and by a grant for Research on Specific Disease from the Ministry of Health, Labor, and Welfare of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 81-89-960-5350; Fax: 81-89-960-5352; E-mail: shirakat{at}m.ehime-u.ac.jp.

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