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Am J Physiol Heart Circ Physiol 275: H1592-H1598, 1998;
0363-6135/98 $5.00
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Vol. 275, Issue 5, H1592-H1598, November 1998

TNF-alpha -induced endothelium-independent vasodilation: a role for phospholipase A2-dependent ceramide signaling

Douglas G. Johns and R. Clinton Webb

Department of Physiology, University of Michigan, Ann Arbor, Michigan 48109

Ceramide is a novel second messenger generated by hydrolysis of membrane sphingomyelin by a neutral sphingomyelinase (nSMase). Cytokines such as tumor necrosis factor-alpha (TNF-alpha ) have been shown to increase intracellular ceramide through phospholipase A2 (PLA2)-dependent activation of nSMase. TNF-alpha 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-alpha -induced vasodilation. In phenylephrine-contracted rat thoracic aortic rings (no endothelium), TNF-alpha 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-alpha -induced relaxation. In cultured rat aortic vascular smooth muscle cells, TNF-alpha (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-alpha -induced endothelium-independent vasodilation.

cytokines; smooth muscle relaxation; sphingolipid signaling; sepsis


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