Activation of multiple signal transduction pathways by endothelin in cultured human vascular smooth muscle cells.
Cellular responses to the vasoconstrictor peptide, endothelin, have been investigated in quiescent cultured human vascular smooth muscle cells (hVSMC). Endothelin caused intracellular alkalinization and activation of the protein synthetic enzyme S6-kinase, but such responses were not associated with any mitogenic effects of endothelin on hVSMC. In myo-[3H]inositol-prelabelled hVSMC endothelin elicited a rapid increase in inositol bis- and tris-phosphates and concomitant hydrolysis of polyphosphoinositol lipids. In [3H]arachidonate-prelabelled hVSMC endothelin promoted production of diacylglycerol, the early kinetics of which parallelled polyphosphoinositol lipid hydrolysis. Such phospholipase C activation by endothelin was sustained in hVSMC with accumulation of inositol polyphosphates being markedly protracted and the decay of diacylglycerol slow. Endothelin promoted extracellular release of [3H]arachidonate-labelled material from hVSMC which derived via deacylation of both phosphatidylinositol and phosphatidylcholine. This process was inhibited by phospholipase A2 and lipoxygenase inhibitors, but insensitive to phospholipase C and cyclooxygenase inhibitors. Endothelin-induced activation of phospholipase C and phospholipase A2 signal transduction pathways (EC50 approximately 5-8 nM for both) in hVSMC apparently proceed in an independent parallel manner rather than a sequential one.
Resink
T J
TJ
Department of Research, University Hospital, Basel, Switzerland.
Scott-Burden
T
T
Bühler
F R
FR
D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D001160:Arterioles / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D004075:Diglycerides / Q000378:metabolism; D016232:Endothelins; D004730:Endothelium, Vascular / Q000502:physiology*; D004789:Enzyme Activation; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D017466:Receptors, Endothelin; D019893:Ribosomal Protein S6 Kinases; D015398:Signal Transduction / Q000187:drug effects*
D001095:Arachidonic Acids; D004075:Diglycerides; D016232:Endothelins; D010455:Peptides; D010716:Phosphatidylinositols; D010743:Phospholipids; D011956:Receptors, Cell Surface; D017466:Receptors, Endothelin; D016718:Arachidonic Acid; D011494:Protein Kinases; D019893:Ribosomal Protein S6 Kinases