Protease-Activated Receptors Upregulate Cyclooxygenase-2 Expression in Human Endothelial Cells

Summary

We have previously shown that the serine protease thrombin and other G protein-coupled agonists acutely enhance synthesis and release of prostacyclin from human umbilical vein endothelial cells (HUVEC) through activation of cPLA₂α. Here, we show that thrombin and other physiological endothelial cell agonists upregulate COX-2 induction in HUVEC. Thrombin treatment caused a rapid and sustained increase in prostacyclin (PGI₂) synthesis from HUVEC. Thrombin and a selective protease-activated receptor-1 (PAR-1) peptide (TRAP) evoked doseand time-dependent increases in COX-2 protein expression which were equivalent to that induced by the proinflammatory cytokine IL-1α. Quantitative and real-time PCR analysis showed enhanced COX-2 mRNA expression in thrombinor TRAP-stimulated HUVEC whereas COX-1 expression was unaffected. A PAR-2 agonist peptide also induced COX-2 protein and mRNA expression with kinetics distinct from those of thrombin, and promoted PGI₂ release. These results demonstrate that regulation of COX-2 induction is an important functional response of HUVEC to PAR activation and suggest that PARs promote sustained upregulation of prostanoid production in human endothelium.

Keywords

Human endothelium - thrombin - cyclooxygenase - prostacyclin - protease-activated receptors

• References

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