title: Lysophosphatidylcholine inhibits surface receptor-mediated intracellular signals in endothelial cells by a pathway involving protein kinase C activation.
abstract: Lysophosphatidylcholine (lysoPC) transferred from oxidatively modified low density lipoprotein (Ox-LDL) to the endothelial surface membrane has been shown to produce a selective unresponsiveness to cell surface receptor-regulated endothelium-dependent relaxation (EDR) in the rabbit aorta. To determine its mechanism we examined the effects of lysoPC on endothelial surface receptor-mediated transmembrane signals. Incubation for 1 minute with palmitoyl lysoPC (5-10 microM) decreased thrombin (Th, 2 units/ml)- or histamine (His, 0.1 mM)-stimulated inositol 1,4,5-trisphosphate (IP3) production in primary cultures of human umbilical vein endothelial cells (HUVECs). LysoPC also decreased Th- or His-induced intracellular calcium ([Ca2+]i, fura 2) elevation. Pretreatment with protein kinase C (PKC) inhibitors staurosporine (100 nM) or H-7 (50 microM) prevented the inhibitory actions of lysoPC, but HA-1004 had no effect. Incubation for 5 minutes with phorbol 12-myristate 13-acetate (PMA, 100 nM) produced the inhibitory actions on the Th- or His-induced intracellular signals, which closely mimic those exhibited by lysoPC. However, the inhibitory effect of lysoPC was lost in cells that were depleted of PKC by pretreatment for 24 hours with 100 nM PMA. Furthermore, incubation of the cells for 1 minute with lysoPC stimulated PKC activity in the membrane fraction. In organ chamber experiments with porcine coronary artery rings, pretreatment with staurosporine (20 nM) attenuated lysoPC-induced impairment of EDR in response to Th. These results indicate that lysoPC, which accumulates in Ox-LDL and atherosclerotic arterial walls, inhibits the early transmembrane signaling pathway in endothelial cells, and PKC activation could at least partially be involved in the negative regulation by lysoPC.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Division of Cardiology, Kumamoto University School of Medicine, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kugiyama
authors.forename: M
authors.initials: M
authors.lastname: Ohgushi
authors.forename: S
authors.initials: S
authors.lastname: Sugiyama
authors.forename: T
authors.initials: T
authors.lastname: Murohara
authors.forename: K
authors.initials: K
authors.lastname: Fukunaga
authors.forename: E
authors.initials: E
authors.lastname: Miyamoto
authors.forename: H
authors.initials: H
authors.lastname: Yasue
mesh_terms: D000818:Animals; D001158:Arteries; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003331:Coronary Vessels; D003600:Cytosol / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D066298:In Vitro Techniques; D015544:Inositol 1,4,5-Trisphosphate / Q000032:analysis; D008244:Lysophosphatidylcholines / Q000494:pharmacology*; D008954:Models, Biological; D011493:Protein Kinase C / Q000032:analysis / Q000378:metabolism*; D013552:Swine; D014471:Umbilical Veins
chemical_list: D008244:Lysophosphatidylcholines; D015544:Inositol 1,4,5-Trisphosphate; D011493:Protein Kinase C; D002118:Calcium