PECAM‐1 modulates thrombin‐induced tissue factor expression on endothelial cells

Abstract

Platelet endothelial cell adhesion molecule-1 (PECAM-1) (CD31) is known to inhibit platelet function and thrombus formation. The mechanisms involved in PECAM-1's roles as a modulator of hemostasis are still not completely understood. We examined the role of PECAM-1 as a regulator of tissue factor (TF) expression, a known important inducer of thrombosis. Wildtype and CD31KO mice underwent transient (30 min) renal ischemia followed by 24 h re-perfusion and their kidneys assessed for apoptosis, fibrin formation, and tissue factor expression. CD31KO mice exhibited increased tubular epithelial and endothelial apoptosis, increased fibrin deposition, and tissue factor expression. Human umbilical vein endothelial cells (HUVEC) transfected with antisense (AS) PECAM-1 oligonucleotides to downregulate PECAM-1 expression, exhibited greater induction of TF mRNA and protein expression as well as increased expression and nuclear localization of the transcription factor Egr-1 compared to scrambled AS PECAM-1 (Scr)-treated HUVEC following thrombin stimulation. TF induction was found to be mediated through thrombin receptor PAR-1 and the Galphai/o subunit of G-protein, confirmed by PAR-1 antagonist and pertussis toxin inhibition respectively. Thrombin-mediated TF induction was dependent on Rho Kinase activity, phosphorylation of p38(MAPK) and p85 & Akt dephosphorylation. The inverse correlation of PI3K-Akt phosphorylation with p38 (MAPK) phosphorylation was confirmed by pharmacological inhibition. These studies suggest that PECAM-1 is involved in regulating a signaling pathway, affecting PI3K and Akt activation, p38 (MAPK) phosphorylation, which in turn, affects Egr-1 expression and nuclear translocation, ultimately affecting TF expression. These findings provide new insights into the action of PECAM-1 as a modulator of thrombosis.

CD44 Regulation of Endothelial Cell Proliferation and Apoptosis via Modulation of CD31 and VE-cadherin Expression

“…These findings support the concept that CD44 mediates several of its effects in endothelia through modulation of cell junctional molecule expression (e.g. CD31 and VE-cadherin), which, in addition to its known modulation of junctional integrity, matrix metalloproteinase levels and activation, interactions with cortical membrane proteins, and selected signaling pathways, modulates proliferation and apoptosis (22)(23)(24)(25)(26)(27)(28)(29), further defining the integrated roles of CD44, VE-cadherin, and CD31 as critical regulators of vascular function.…”

Platelet Activation in Cats with Hypertrophic Cardiomyopathy

“…PECAM‐1 has been shown to have proinflammatory activity through the promotion of leukocyte‐endothelial translocation and transmission of systemic signals associated with endothelial stress 37. Unlike platelet P‐selectin, which supports neutrophil‐platelet and platelet‐endothelial interactions, platelet PECAM is an inhibitory molecule that has been proposed to limit thrombus formation by limiting platelet‐platelet interactions as well as platelet adhesion to collagen 34, 38, 39. These studies have suggested that PECAM‐1 serves to regulate thrombus formation and thereby inhibit vessel occlusion.…”

Tissue Factor and Cardiovascular Disease: Quo Vadis?

“…The above mentioned mediators stimulate, after binding to their corresponding receptor, the MAP kinases p38, ERK, and c-jun terminal NH2-kinase with downstream activation of transcription factors such as NFκB, AP-1 or EGR-1. [20][21][22] Also the protein kinase C as well as the Rho-Kinase pathway 17,23 are known to mediate TF induction. In contrast, the PI3 kinase pathway and its downstream target Akt, GSK-3β, and the mammalian target of rapamycin inhibit TF expression either at the transcriptional or the translational level.…”