Soluble thrombomodulin is a paracrine anti-apoptotic factor for vascular endothelial protection.
BACKGROUND
Thrombomodulin (TM) is an endothelial cell (EC) membrane-bound anticoagulant protein that has novel direct cellular effects. TM is shed from EC and becomes soluble form (sTM) in plasma. Higher sTM levels in healthy subjects are associated with lower cardiovascular risk, suggesting that sTM possesses a protective role. The purpose of the study was to evaluate the effect of sTM on vascular endothelium.


RESULTS
Apoptosis of cultured ECs was induced via serum starvation. EC-bound TM was released into the medium after serum starvation. The medium conditioned by serum-starved EC decreased apoptosis in another set of cultured EC. Direct treatment with sTM reduced EC apoptosis and decreased pro-apoptotic protein expression. TM knockdown in EC exacerbated the rate of serum starvation-induced apoptosis. Treatment of sTM activated the phosphatidylinositol 3-kinase (PI3 kinase)-protein kinase B/Akt survival pathway and suppressed the death pathway, c-Jun N-terminal kinase. We found that sTM also increased growth and reduced apoptosis of endothelial progenitor cells.


CONCLUSIONS
EC-bound TM is released during stress-induced EC damage and becomes sTM, a paracrine factor that exerts anti-apoptotic activity. Our data indicate that sTM is not only an endothelial injury biomarker but also has cytoprotective effects on vascular endothelium.
Department of Internal Medicine, Hospital and College of Medicine, National Cheng Kung University, Tainan, Taiwan; Cardiovascular Research Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Ting-Hsing
TH
Chao
Department of Internal Medicine, Hospital and College of Medicine, National Cheng Kung University, Tainan, Taiwan; Cardiovascular Research Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Wei-Chuan
WC
Tsai
Department of Internal Medicine, Hospital and College of Medicine, National Cheng Kung University, Tainan, Taiwan; Cardiovascular Research Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Ju-Yi
JY
Chen
Department of Internal Medicine, Hospital and College of Medicine, National Cheng Kung University, Tainan, Taiwan; Cardiovascular Research Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Ping-Yen
PY
Liu
Department of Internal Medicine, Hospital and College of Medicine, National Cheng Kung University, Tainan, Taiwan; Cardiovascular Research Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Hsing-Chun
HC
Chung
Department of Internal Medicine, Hospital and College of Medicine, National Cheng Kung University, Tainan, Taiwan; Cardiovascular Research Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Shi-Ya
SY
Tseng
Cardiovascular Research Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Cheng-Hsiang
CH
Kuo
Cardiovascular Research Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Guey-Yueh
GY
Shi
Cardiovascular Research Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Hua-Lin
HL
Wu
Department of Internal Medicine, Hospital and College of Medicine, National Cheng Kung University, Tainan, Taiwan; Cardiovascular Research Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Electronic address: heng@mail.ncku.edu.tw.
Yi-Heng
YH
Li
D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D020287:In Situ Nick-End Labeling; D015398:Signal Transduction / Q000187:drug effects; D018180:Thrombomodulin / Q000378:metabolism / Q000502:physiology*; D014470:Umbilical Cord / Q000166:cytology
D017077:Culture Media, Conditioned; D018180:Thrombomodulin
Apoptosis; Endothelium; Thrombomodulin