Molecular mechanisms of thrombin-induced human and bovine endothelial cell activation.
Thrombin, the key regulatory protein of hemostasis, is a potent stimulus for endothelial cell activation, a process implicated in a variety of ischemic, thrombotic, and inflammatory vascular disorders. Activation of the thrombin receptor requires a novel mechanism of receptor proteolysis generating a tethered receptor ligand. Synthetic peptides whose sequences are identical to this newly exposed receptor NH2-terminus reproduce thrombin effects on human and bovine endothelial cell activation. Receptor cleavage by catalytically active alpha-thrombin is tightly coupled to a PI-PLC, with resultant generation of IP3 and DAG, increases in [Ca2+]i, and translocation of PKC (Fig. 3). Both the increase in [Ca2+]i and PKC activation are required for thrombin-stimulated PLA2 and PLD activity, PGI2 synthesis, and barrier dysfunction, the latter occurring as the result of Ca2+ and PKC effects on specific cytoskeletal protein elements and other contractile proteins (Fig. 3). Further investigations are ongoing to identify more clearly not only the precise biochemical intermediates involved in the endothelial cell response to thrombin but also the specific protein kinase systems involved in thrombin-mediated signal transduction in vascular endothelium.
Garcia
J G
JG
Department of Medicine, Indiana University School of Medicine, Indianapolis.
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002417:Cattle; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology*; D011464:Epoprostenol / Q000096:biosynthesis; D006801:Humans; D010716:Phosphatidylinositols / Q000378:metabolism; D010740:Phospholipases / Q000378:metabolism; D013917:Thrombin / Q000494:pharmacology*
D010716:Phosphatidylinositols; D011464:Epoprostenol; D010740:Phospholipases; D013917:Thrombin; D002118:Calcium