Lysophosphatidylcholine modifies G protein-dependent signaling in porcine endothelial cells.
Certain endothelial receptors are coupled to a pertussis toxin-sensitive inhibitory guanine nucleotide-binding regulatory (Gi) protein. In pigs, hypercholesterolemia causes a selective impairment of this Gi protein-dependent pathway. Recent studies have suggested that hypercholesterolemia-induced endothelial dysfunction may be caused by lysophosphatidylcholine (LPC) derived from oxidized low-density lipoprotein (LDL). The aim of the present study was to determine whether LPC could inhibit the Gi protein-dependent pathway. Isolated rings of porcine coronary arteries were suspended for isometric tension recording in organ chambers filled with physiological salt solution (37 degrees C, 95% O2-5% CO2). In rings with endothelium contracted with prostaglandin F2 alpha, pertussis toxin (100 ng/ml) or LPC (10(-5) M) inhibited the endothelium-dependent relaxations evoked by UK-14,304, an alpha 2-adrenergic agonist, or by serotonin, but not those caused by bradykinin or ADP. LPC also did not inhibit relaxations produced by SIN 1, an endothelium-derived relaxing factor-nitric oxide donor. After treatment of the rings with pertussis toxin, LPC no longer inhibited the endothelium-dependent relaxations to serotonin. Although LPC inhibited the responses of membrane-bound receptors that activate the pertussis toxin-sensitive Gi protein, LPC did not affect the endothelium-dependent relaxations evoked by direct activation of the pertussis toxin-sensitive Gi protein by fluoride. These results suggest that LPC selectively inhibits a Gi protein-dependent pathway in porcine endothelial cells possibly by disrupting receptor-G protein interactions. LPC that is associated with oxidized LDL may mediate in part the dysfunction in the endothelial Gi protein-dependent pathway associated with hypercholesterolemia.
Flavahan
N A
NA
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D000068438:Brimonidine Tartrate; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology; D015237:Dinoprost / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D005260:Female; D005459:Fluorides / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000502:physiology*; D008244:Lysophosphatidylcholines / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D037342:Pertussis Toxin; D011810:Quinoxalines / Q000494:pharmacology; D012701:Serotonin / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D013552:Swine; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D008244:Lysophosphatidylcholines; D011810:Quinoxalines; D010566:Virulence Factors, Bordetella; D012701:Serotonin; D000068438:Brimonidine Tartrate; D000244:Adenosine Diphosphate; D015237:Dinoprost; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D005459:Fluorides; D001920:Bradykinin