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Am. J. Respir. Cell Mol. Biol., Volume 24, Number 6, June, 2001 762-768

Rapid Reactive Oxygen Species Production by Mitochondria in Endothelial Cells Exposed to Tumor Necrosis Factor-alpha Is Mediated by Ceramide

Stefano Corda, Christian Laplace, Eric Vicaut, and Jacques Duranteau

Laboratoire d'Anesthésie-Réanimation, Université Paris XI, Hôpital de Bicêtre, Assistance Publique-Hôpitaux de Paris, Le Kremlin Bicêtre; and Laboratoire d'Etude de la Microcirculation et Département de Biophysique Université Paris VII, Hôpital F. Widal, Paris, France

Tumor necrosis factor (TNF)-alpha increases mitochondrial reactive oxygen species (ROS) production in tumor cells and hepatocytes. However, whether TNF-alpha stimulates mitochondrial ROS production in endothelial cells (EC) has not yet been reported. We studied the effect of TNF-alpha on mitochondrial ROS generation in EC and the signaling pathways involved. Cultured human umbilical vein EC (HUVEC) were studied by fluorescence microscopy, using dichlorodihydrofluorescein diacetate (DCFH-DA) as a marker of ROS production and propidium iodide uptake for cell viability. TNF-alpha increased DCFH oxidation in HUVEC dose-dependently. To determine the source of ROS, the mitochondrial respiratory chain inhibitors rotenone + thenoyltrifluoroacetone (TTFA), which inhibit electron entry to ubiquinone, and antimycin A (AA), a blocker of ubisemiquinone, were used. Rotenone and TTFA inhibited (n = 7, P < 0.05), whereas AA increased (118% in 3 min; n = 4, P < 0.01) ROS generation in HUVEC. In contrast, ROS production was not abolished by the nicotinamide adenine dinucleotide phosphate-dependent oxidase inhibitor diphenylene iodonium, by the xanthine oxidase inhibitor allopurinol, nor by the nitric oxide and cyclooxygenase pathway inhibitors Nomega -nitro-L-arginine and mefenamic acid. In addition, TNF-alpha -induced ROS production was inhibited by the acidic sphingomyelinase inhibitor desipramine (5 µM; -80%, n = 4, P < 0.01) and totally blocked by the ceramide-activated protein kinase (CAPK) inhibitor dimethylaminopurine (1 mM; n = 6, P < 0.05). Thus, TNF-alpha induces mitochondrial ROS production in HUVEC that primarily occurs at the ubisemiquinone site and is mediated by ceramide-dependent signaling pathways involving CAPK.

Abbreviations: antimycin A, AA; acidic sphingomyelinase, ASMase; ceramide-activated protein kinase, CAPK; 2,7-dichlorofluorescein, DCF; dichlorodihydrofluorescein, DCFH; dichlorodihydrofluorescein diacetate, DCFH-DA; dimethylaminopurine, DMAP; diphenylene iodonium, DPI; human umbilical vein endothelial cells, HUVEC; Nomega -nitro-L-arginine, L-NNA; nicotinamide adenine dinucleotide reduced, NADH; nicotinamide adenine dinucleotide phosphate, NADPH; nitric oxide, NO; nitric oxide synthase, NOS; propidium iodide, PI; reactive oxygen species, ROS; standard error of the mean, SEM; tumor necrosis factor alpha, TNF-alpha ; thenoyltrifluoroacetone, TTFA; xanthine oxidase, XO.




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