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Published on: February 13, 2013
PECAM-1 modulates thrombin-induced tissue factor expression on endothelial cells.
Jenny J Zhang1, Robert J Kelm, Purba Biswas
1Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Journal of Cellular Physiology
|November 18, 2006
Summary
Platelet endothelial cell adhesion molecule-1 (PECAM-1) inhibits thrombosis by regulating tissue factor (TF) expression. Downregulating PECAM-1 increases TF, impacting hemostasis and potentially leading to thrombosis.
Area of Science:
- Vascular Biology
- Hemostasis and Thrombosis
- Molecular Signaling
Background:
- Platelet endothelial cell adhesion molecule-1 (PECAM-1), also known as CD31, is recognized for its inhibitory role in platelet function and thrombus formation.
- The precise mechanisms by which PECAM-1 modulates hemostasis remain incompletely elucidated.
Purpose of the Study:
- To investigate the role of PECAM-1 in regulating tissue factor (TF) expression, a key initiator of thrombosis.
- To elucidate the signaling pathways involved in PECAM-1-mediated regulation of TF.
Main Methods:
- Utilized wildtype and CD31 knockout (CD31KO) mice subjected to renal ischemia-reperfusion injury to assess apoptosis, fibrin deposition, and TF expression.
- Employed human umbilical vein endothelial cells (HUVEC) treated with antisense oligonucleotides to downregulate PECAM-1 and examined TF induction, Egr-1 expression, and downstream signaling pathways.
- Investigated the involvement of PAR-1, G-protein signaling, Rho Kinase, p38(MAPK), and PI3K-Akt pathways using pharmacological inhibitors and antagonists.
Main Results:
- CD31KO mice displayed elevated tubular epithelial and endothelial apoptosis, increased fibrin deposition, and heightened TF expression compared to wildtype controls.
- Downregulation of PECAM-1 in HUVECs resulted in significantly greater induction of TF mRNA and protein, alongside increased Egr-1 expression and nuclear translocation.
- Thrombin-induced TF expression was mediated via PAR-1 and G-protein signaling, dependent on Rho Kinase activity, p38(MAPK) phosphorylation, and Akt dephosphorylation, with an inverse correlation between PI3K-Akt and p38(MAPK) phosphorylation.
Conclusions:
- PECAM-1 plays a crucial role in modulating a signaling cascade that impacts PI3K/Akt activation, p38(MAPK) phosphorylation, and subsequent Egr-1 and TF expression.
- These findings reveal novel insights into PECAM-1's function as a regulator of thrombosis by influencing key pro-thrombotic pathways.
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