Mitogen-Activated Protein Kinases and Endothelial Prostacyclin Secretion

Abstract

Endothelial cells play an important role in hemostasis and in the modulation of vascular tone. Prostacyclin (PGI₂), a major eicosanoid produced by endothelial cells, is a potent vasorelaxant and inhibitor of platelet aggregation (1). As with other eicosanoids, PGI₂ is biosynthesized from free arachidonic acid (AA) released from membrane phospholipids, primarily through the enzymatic action of cytosolic phospholipase A₂ (cPLA₂) (1, 2). It has been suggested that phosphorylation of specific sites on the enzyme by the 42 kDa mitogen-activated protein (p42 MAP) kinase may be important events leading to cPLA₂ activation (2). We have shown in cultured bovine aortic endothelial cells that agonist-induced PGI₂ secretion occurs in the presence of increased phosphorylation of the low molecular weight 27 kDa heat shock proteins (HSP27) and its isoelectric variants (3, 4). It is now known that the phosphorylation of HSP27 is directly controlled by MAP kinase activated protein kinase-2 (MAPKAP K-2), which itself is modulated by a 38 kDa homologue (p38 MAP kinase) of p42MAP kinase (5). Experiments included in this chapter are focused on studying the interaction between p38 and p42MAP kinases during BK modulation of PGI₂ secretion in the same cell model.