Vitamin k epoxide reductase: a protein involved in angiogenesis.
Vitamin K epoxide reductase (VKOR) is a newly identified protein which has been reported to convert the epoxide of vitamin K back to vitamin K, a cofactor essential for the posttranslational gamma-carboxylation of several blood coagulation factors. We found that the gene is expressed ubiquitously including vascular endothelial cells, smooth muscle cells, fibroblasts and cardiomyocytes, and is overexpressed in 11 tumor tissues on microarray. Stable transfection of VKOR cDNA into tumor cell line A549 and H7402 did not promote the cell proliferation. These results promoted us to hypothesize that VKOR may also be involved in angiogenesis. To test this hypothesis, the expression of VKOR was studied in different vascular cells in developmental and pathologic heart tissues. The effects of overexpression and suppressing expression of VKOR on endothelial cell proliferation, migration, adhesion, and tubular network formation were explored. We found that VKOR expression in arteries was prominent in vascular endothelial cells and was high in the ventricular aneurysm tissue of human heart and human fetal heart. In vitro studies showed that overexpression of VKOR slightly but significantly stimulated human umbilical vein endothelial cell proliferation (by 120%), migration (by 118%), adhesion (by 117%), as well as tubular network formation. Antisense to VKOR gene inhibited the proliferation (by 67%), migration (by 64%), adhesion (by 50%), and tubular network formation. Our findings support the impact of VKOR in the process of angiogenesis; hence, the molecule may have a potential application in cardiovascular disease and cancer therapy.
Sino-German Laboratory for Molecular Medicine and Hypertension Division, Cardiovascular Institute and Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishilu, Xicheng District, Beijing 100037, P.R. China.
Yibo
Y
Wang
Yisong
Y
Zhen
Yi
Y
Shi
Jingzhou
J
Chen
Channa
C
Zhang
Xiaojian
X
Wang
Xu
X
Yang
Yi
Y
Zheng
Yuqing
Y
Liu
Rutai
R
Hui
D000256:Adenoviridae / Q000235:genetics; D000783:Aneurysm / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D001011:Aorta / Q000166:cytology; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005333:Fetus; D005786:Gene Expression Regulation; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000502:physiology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D038081:Organogenesis / Q000187:drug effects; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D014018:Tissue Distribution; D014162:Transfection; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D064417:Vitamin K Epoxide Reductases
D016376:Oligonucleotides, Antisense; D011506:Proteins; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D006899:Mixed Function Oxygenases; D064417:Vitamin K Epoxide Reductases