Forkhead factor, FOXO3a, induces apoptosis of endothelial cells through activation of matrix metalloproteinases.
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.


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.


CONCLUSIONS
Activation of MMPs and possible ECM disruption represent novel mechanisms of FOXO3a-mediated apoptosis in ECs.
Lee
Hae-Young
HY
Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Korea.
You
Hyun-Jung
HJ
Won
Joo-Yun
JY
Youn
Seock-Won
SW
Cho
Hyun-Jai
HJ
Park
Kyung-Woo
KW
Park
Woong-Yang
WY
Seo
Jeong-Sun
JS
Park
Young-Bae
YB
Walsh
Kenneth
K
Oh
Byung-Hee
BH
Kim
Hyo-Soo
HS
D000818:Animals; D023102:Anoikis / Q000502:physiology; D017209:Apoptosis / Q000502:physiology*; D002339:Carotid Arteries / Q000502:physiology; D002448:Cell Adhesion / Q000502:physiology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000502:physiology*; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000502:physiology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000502:physiology*; D006801:Humans; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism*; D011817:Rabbits; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*; D014471:Umbilical Veins / Q000166:cytology
C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D019715:Tissue Inhibitor of Metalloproteinase-1; D019278:Matrix Metalloproteinase 3