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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:302.)
© 2008 American Heart Association, Inc.

Cell Biology/Signaling

Forkhead Factor, FOXO3a, Induces Apoptosis of Endothelial Cells Through Activation of Matrix Metalloproteinases

Hae-Young Lee; Hyun-Jung You; Joo-Yun Won; Seock-Won Youn; Hyun-Jai Cho; Kyung-Woo Park; Woong-Yang Park; Jeong-Sun Seo; Young-Bae Park; Kenneth Walsh; Byung-Hee Oh; Hyo-Soo Kim

From the Innovative Research Institute for Cell Therapy (H.Y.L., H.J.Y., J.Y.W., S.W.Y., H.J.C., K.W.P., Y.B.P., H.S.K.), Seoul National University Hospital, and the Department of Internal Medicine (H.Y.L., H.J.C., K.W.P., Y.B.P., B.H.O., H.S.K.) and the Department of Biochemistry and Molecular Biology (W.-Y.P., J.-S.S.), Seoul National University College of Medicine, Seoul, Korea; and the Whitaker Cardiovascular Institute (K.W.), Boston University School of Medicine, Boston, Mass.

Correspondence to Hyo-Soo Kim, MD, PhD, Department of Internal Medicine, Seoul National University College of Medicine, 28 Yongon-dong Chongno-gu Seoul 110-744 Korea. E-mail hyosoo{at}snu.ac.kr

Abstract

Background— The forkhead factor, FOXO3a, is known to induce apoptosis in endothelial cells (ECs). However, its effects on extracellular matrices (ECM), which are important in EC survival, remained unknown. Here, we evaluated the role of FOXO3a on EC-ECM interaction.

Methods and Results— Constitutively active FOXO3a was transduced to human umbilical vein endothelial cells by adenoviral vector (Ad-TM-FOXO3a). Ad-TM-FOXO3a transfection led to dehiscence of ECs from fibronectin-coated plates, resulting in anoikis, which was significantly reversed by matrix metalloproteinase (MMP) inhibitor, GM6001. FOXO3a increased the expression of MMP-3 (stromelysin-1) but decreased the expression of tissue inhibitors of metalloproteinases-1 (TIMP-1), which was associated with increased MMP enzymatic activity in zymography. Pathophysiologic conditions such as serum starvation or heat shock also induced activation of endogenous FOXO3a, leading to activation of MMP-3 and apoptosis, which was reversed by GM6001. Delivery of Ad-TM-FOXO3a to the intraluminal surface in vivo led to EC denudation, disrupted vascular integrity, and impaired endothelium-dependent vasorelaxation.

Conclusion— Activation of MMPs and possible ECM disruption represent novel mechanisms of FOXO3a-mediated apoptosis in ECs.

The forkhead factor, FOXO3a, is known to induce apoptosis in endothelial cells. Here, we evaluated the role of FOXO3a on endothelial cells-extracellular matrix interactions. We found activation of MMPs and possible ECM disruption represent novel mechanisms of FOXO3a-mediated apoptosis in endothelial cells.

Key Words: FOXO3a • MMP • endothelial cell • apoptosis