Lysophosphatidylcholine inhibits surface receptor-mediated intracellular signals in endothelial cells by a pathway involving protein kinase C activation.
- 1 December 1992
- journal article
- research article
- Published by Wolters Kluwer Health in Circulation Research
- Vol. 71 (6) , 1422-1428
- https://doi.org/10.1161/01.res.71.6.1422
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)Keywords
This publication has 25 references indexed in Scilit:
- The effect of phenylephrine on inositol 1,4,5-trisphosphate levels in vascular smooth muscle measured using a protein binding assay systemBiochemical and Biophysical Research Communications, 1990
- Evidence for the presence of oxidatively modified low density lipoprotein in atherosclerotic lesions of rabbit and man.Journal of Clinical Investigation, 1989
- Beyond CholesterolNew England Journal of Medicine, 1989
- Thrombin and histamine activate phospholipase C in human endothelial cells via a phorbol ester‐sensitive pathwayJournal of Cellular Physiology, 1988
- Rapid purification of protein kinase C from rat brainEuropean Journal of Biochemistry, 1987
- Impaired muscarinic endothelium-dependent relaxation and cyclic guanosine 5'-monophosphate formation in atherosclerotic human coronary artery and rabbit aorta.Journal of Clinical Investigation, 1987
- The Metabolism of Phosphoinositide-Derived Messenger MoleculesScience, 1986
- Staurosporine, a potent inhibitor of phospholipidCa++dependent protein kinaseBiochemical and Biophysical Research Communications, 1986
- Phorbol esters and vasopressin stimulate DNA synthesis by a common mechanismNature, 1980
- A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye bindingAnalytical Biochemistry, 1976