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

Research output: Contribution to journalArticle

29 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)302-308
Number of pages7
JournalArteriosclerosis, thrombosis, and vascular biology
Volume28
Issue number2
DOIs
StatePublished - Feb 1 2008

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Matrix Metalloproteinases
Endothelial Cells
Apoptosis
Matrix Metalloproteinase 3
Extracellular Matrix
Anoikis
Tissue Inhibitor of Metalloproteinase-1
Matrix Metalloproteinase Inhibitors
Human Umbilical Vein Endothelial Cells
Starvation
Fibronectins
Vasodilation
Endothelium
Transfection
Blood Vessels
Shock
Cell Survival
Hot Temperature
Serum

Keywords

  • Apoptosis
  • Endothelial cell
  • FOXO3a
  • MMP

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Forkhead factor, FOXO3a, induces apoptosis of endothelial cells through activation of matrix metalloproteinases. / Lee, Hae Young; You, Hyun Jung; Won, Joo Yun; Youn, Seock Won; Cho, Hyun Jai; Park, Kyung Woo; Park, Woong Yang; Seo, Jeong Sun; Park, Young Bae; Walsh, Kenneth; Oh, Byung Hee; Kim, Hyo Soo.

In: Arteriosclerosis, thrombosis, and vascular biology, Vol. 28, No. 2, 01.02.2008, p. 302-308.

Research output: Contribution to journalArticle

Lee, HY, You, HJ, Won, JY, Youn, SW, Cho, HJ, Park, KW, Park, WY, Seo, JS, Park, YB, Walsh, K, Oh, BH & Kim, HS 2008, 'Forkhead factor, FOXO3a, induces apoptosis of endothelial cells through activation of matrix metalloproteinases', Arteriosclerosis, thrombosis, and vascular biology, vol. 28, no. 2, pp. 302-308. https://doi.org/10.1161/ATVBAHA.107.150664
Lee, Hae Young ; You, Hyun Jung ; Won, Joo Yun ; Youn, Seock Won ; Cho, Hyun Jai ; Park, Kyung Woo ; Park, Woong Yang ; Seo, Jeong Sun ; Park, Young Bae ; Walsh, Kenneth ; Oh, Byung Hee ; Kim, Hyo Soo. / Forkhead factor, FOXO3a, induces apoptosis of endothelial cells through activation of matrix metalloproteinases. In: Arteriosclerosis, thrombosis, and vascular biology. 2008 ; Vol. 28, No. 2. pp. 302-308.
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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.",
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AU - Lee, Hae Young

AU - You, Hyun Jung

AU - Won, Joo Yun

AU - Youn, Seock Won

AU - Cho, Hyun Jai

AU - Park, Kyung Woo

AU - Park, Woong Yang

AU - Seo, Jeong Sun

AU - Park, Young Bae

AU - Walsh, Kenneth

AU - Oh, Byung Hee

AU - Kim, Hyo Soo

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N2 - 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.

AB - 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.

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