Analysis of lysophophatidylcholine-induced endothelial dysfunction

J. E. Freeman, W. Y. Kuo, B. Drenger, T. N. Barnett, M. A. Levine, N. A. Flavahan

Research output: Contribution to journalArticle

Abstract

Endothelial dysfunction caused by the early atherosclerotic process or by endothelial exposure to atherogenic lipids, including lysophosphatidylcholine (lysoPC), is characterized by a selective impairment of responses mediated by the pertussis toxin-sensitive G(i-2) protein. Experiments were performed to analyze the mechanisms underlying this effect. Bradykinin (BK: G(i-2) protein-independent), serotonin (5-HT: G(i-2) protein- dependent), or direct activation of the G(i-2)-protein by mastoparan increased the release of endothelium-derived nitric oxide (EDNO) from porcine arterial endothelial cells (EC). LysoPC decreased the release of EDNO caused by 5-HT, but did not affect the response to BK or mastoparan. LysoPC did not increase production of superoxide radicals detected by lucigenin-enhanced chemiluminescence. Western blot analysis showed no difference in the level of immunoreactive G(iα-2) between control and lysoPC-treated cells. Activation of the G(i-2) protein by serotonergic or α2-adrenoceptor stimulation decreased the pertussis toxin-catalyzed ADP-ribosylation of G(iα-2) protein in membranes from control but not lysoPC-treated cells. However, direct activation of the G(i-2) protein by mastoparan inhibited the ADP- ribosylation in membranes from control and lysoPC-treated cells. The toxin- catalyzed reaction was reduced in lysoPC-treated cells or lysoPC-treated membranes. LysoPC reduced the ability of endothelin to increase GTPγS binding to the G(i-2) protein but did not affect the activity of mastoparan. These results suggest that lysoPC inhibits a pertussis toxin-sensitive signaling pathway in EC by an effect consistent with receptor:G(i-2)-protein uncoupling.

Original languageEnglish (US)
Pages (from-to)345-352
Number of pages8
JournalJournal of cardiovascular pharmacology
Volume28
Issue number3
DOIs
StatePublished - Oct 2 1996

Keywords

  • Endothelial dysfunction
  • Hypercholesterolemia
  • Modified lipoproteins
  • Nitric oxide
  • Superoxide anion
  • Western blot

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

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