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J. Biol. Chem., Vol. 280, Issue 36, 31841-31849, September 9, 2005

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Angiopoietin-1 Attenuates H₂O₂-induced SEK1/JNK Phosphorylation through the Phosphatidylinositol 3-Kinase/Akt Pathway in Vascular Endothelial Cells^*

Tomoaki Murakami, Hitoshi Takagi, Kiyoshi Suzuma, Izumi Suzuma, Hirokazu Ohashi, Daisuke Watanabe, Tomonari Ojima, Eri Suganami, Masafumi Kurimoto, Hideaki Kaneto¶, Yoshihito Honda, and Nagahisa Yoshimura

From the Department of Ophthalmology and Visual Sciences Graduate School of Medicine, Kyoto University, 54 Shogoin Kawaharacho Sakyo-ku, Kyoto 606-8507 and the ^¶Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan

Oxidative stress activates various signal transduction pathways, including Jun N-terminal kinase (JNK) and its substrates, that induce apoptosis. We reported here the role of angiopoietin-1 (Ang1), which is a prosurvival factor in endothelial cells, during endothelial cell damage induced by oxidative stress. Hydrogen peroxide (H₂O₂) increased apoptosis of endothelial cells through JNK activation, whereas Ang1 inhibited H₂O₂-induced apoptosis and concomitant JNK phosphorylation. The inhibition of H₂O₂-induced JNK phosphorylation was reversed by inhibitors of phosphatidylinositol (PI) 3-kinase and dominant-negative Akt, and constitutively active-Akt attenuated JNK phosphorylation without Ang1. These data suggested that Ang1-dependent Akt phosphorylation through PI 3-kinase leads to the inhibition of JNK phosphorylation. H₂O₂-induced phosphorylation of SAPK/Erk kinase (SEK1) at Thr²⁶¹, which is an upstream regulator of JNK, was also attenuated by Ang1-dependent activation of the PI 3-kinase/Akt pathway. In addition, Ang1 induced SEK1 phosphorylation at Ser⁸⁰, suggesting the existence of an additional signal transduction pathway through which Ang1 attenuates JNK phosphorylation. These results demonstrated that Ang1 attenuates H₂O₂-induced SEK1/JNK phosphorylation through the PI 3-kinase/Akt pathway and inhibits the apoptosis of endothelial cells to oxidative stress.

Received for publication, March 21, 2005 , and in revised form, July 5, 2005.

^* This work was supported by Grants-in-aid for Scientific Research 70283596 from the Ministry of Education, Science, and Culture and the Ministry of Health and Welfare of the Japanese Government. 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.

To whom correspondence should be addressed: Dept. of Ophthalmology and Visual Sciences Graduate School of Medicine, Kyoto University, 54 Shogoin Kawaharacho Sakyo-ku, Kyoto 606-8507, Japan. Tel.: 81-75-751-3251; Fax: 81-75-752-0933; E-mail: hitoshi{at}kuhp.kyoto-u.ac.jp.

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