TNF-α-induced endothelium-independent vasodilation: A role for phospholipase A2-dependent ceramide signaling

Douglas G. Johns, R. Clinton Webb

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

Ceramide is a novel second messenger generated by hydrolysis of membrane sphingomyelin by a neutral sphingomyelinase (nSMase). Cytokines such as tumor necrosis factor-α (TNF-α) have been shown to increase intracellular ceramide through phospholipase A2 (PLA2)-dependent activation of nSMase. TNF-α has been shown to cause endothelium-independent relaxation in isolated blood vessels. We have previously shown that exogenously applied sphingomyelinase and ceramide cause endothelium-independent vasodilation in rat thoracic aortas (D. G. Johns, H. Osborn, and R. C. Webb. Biochem. Biophys. Res. Commun. 237: 95-97, 1997). In the present study, we tested the hypothesis that ceramide mediates TNF-α-induced vasodilation. In phenylephrine-contracted rat thoracic aortic rings (no endothelium), TNF-α caused concentration-dependent relaxation in the presence of cyclooxygenase and lipoxygenase inhibitors. The phospholipase A2 antagonist 7,7-dimethyl- (5Z,8Z)-eicosadienoic acid (DEDA; 50 μM) and the nonselective PLA2 antagonist quinacrine (30 μM) inhibited TNF-α-induced relaxation. In cultured rat aortic vascular smooth muscle cells, TNF-α (10-7 g/ml) increased intracellular ceramide 1.5-fold over basal level (0.08 nmol/mg protein), which was blocked by the PLA2 antagonist DEDA (50 μM). We conclude that PLA2 activation and increased ceramide generation play a role in mediating TNF-α-induced endothelium-independent vasodilation.

Original languageEnglish (US)
Pages (from-to)H1592-H1598
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume275
Issue number5
DOIs
StatePublished - Nov 1 1998

Keywords

  • Cytokines
  • Sepsis
  • Smooth muscle relaxation
  • Sphingolipid signaling

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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