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 language | English (US) |
|---|---|
| Journal | American Journal of Physiology - Heart and Circulatory Physiology |
| Volume | 275 |
| Issue number | 5 |
| State | Published - Nov 1 1998 |
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Keywords
- Cytokines
- Sepsis
- Smooth muscle relaxation
- Sphingolipid signaling
ASJC Scopus subject areas
- Physiology
- Physiology (medical)
Cite this
TNF-α-induced endothelium-independent vasodilation : A role for phospholipase A2-dependent ceramide signaling. / Johns, Douglas G.; Webb, R. Clinton.
In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 275, No. 5, 01.11.1998.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - TNF-α-induced endothelium-independent vasodilation
T2 - A role for phospholipase A2-dependent ceramide signaling
AU - Johns, Douglas G.
AU - Webb, R. Clinton
PY - 1998/11/1
Y1 - 1998/11/1
N2 - 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.
AB - 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.
KW - Cytokines
KW - Sepsis
KW - Smooth muscle relaxation
KW - Sphingolipid signaling
UR - http://www.scopus.com/inward/record.url?scp=0031755713&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0031755713&partnerID=8YFLogxK
M3 - Article
C2 - 9815065
AN - SCOPUS:0031755713
VL - 275
JO - American Journal of Physiology - Heart and Circulatory Physiology
JF - American Journal of Physiology - Heart and Circulatory Physiology
SN - 0363-6135
IS - 5
ER -