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J. Biol. Chem., Vol. 281, Issue 28, 19009-19018, July 14, 2006

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C5b-9-induced Endothelial Cell Proliferation and Migration Are Dependent on Akt Inactivation of Forkhead Transcription Factor FOXO1^*

Matthew Fosbrink¹, Florin Niculescu, Violeta Rus, Moon L. Shin^¶, and Horea Rus²

From the Departments of Neurology and Medicine, Division of Rheumatology and Clinical Immunology, and ^¶Pathology, University of Maryland School of Medicine, Baltimore, Maryland 21201

Migration and proliferation of aortic endothelial cells (AEC) are critical processes involved in angiogenesis, atherosclerosis, and postangioplasty restenosis. Activation of complement and assembly of the C5b-9 complement complex have been implicated in the pre-lesional stage of atherogenesis and progression of the atherosclerotic lesion. We have shown that C5b-9 induces proliferation and activates phosphatidylinositol 3-kinase (PI3K), but it is unknown whether this can lead to activation of Akt in AEC, a major downstream target of PI3K, or if C5b-9 can induce the migration of AEC, a critical step in angiogenesis. In this study, we show that C5b-9 induces AEC proliferation and migration and also activates the PI3K/Akt pathway. C5b-9 activates Akt as shown by in vitro kinase assay and phosphorylation of Ser-473. C5b-9-induced cell cycle activation was inhibited by pretreatment with LY294002 (PI3K inhibitor), SH-5 (Akt inhibitor), or transfection with Akt siRNA. These data suggests that the PI3K/Akt pathway is required for C5b-9-induced cell cycle activation. FOXO1, a member of forkhead transcription factor family, was phosphorylated at Ser-256 and inactivated after C5b-9 stimulation as shown by a decrease in DNA binding and cytoplasmic relocalization. Cytoplasmic relocalization was significantly reduced after pretreatment with LY294002, SH-5, or transfection with Akt siRNA. Silencing FOXO1 expression using siRNA stimulated AEC proliferation and regulated angiogenic factor release. Our data indicate that C5b-9 regulation of the cell cycle activation in AEC through Akt pathway is dependent on inactivation of FOXO1.

Received for publication, March 3, 2006 , and in revised form, May 1, 2006.

^* This work was supported in part by United States Public Health Grant RO-1 NS42011 (to H. R.) and the Veterans Administration Maryland Health Care System, Multiple Sclerosis Center of Excellence, Baltimore, MD (to H. R.). 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 Supported in part by National Institutes of Health Training Grant ES 07263.

² To whom correspondence should be addressed: Dept. of Neurology, University of Maryland School of Medicine, 655 W. Baltimore St., BRB 12-014, Baltimore, MD 21201. Tel.: 410-706-3170; Fax: 410-706-0186; E-mail: hrus{at}umaryland.edu.

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