Daunorubicin attenuates tumor necrosis factor-alpha-induced biosynthesis of plasminogen activator inhibitor-1 in human umbilical vein endothelial cells

The anthracycline antibiotic daunorubicin is reported to induce apoptosis i n cells by triggering ceramide generation through de novo synthesis or sphi ngomyelin hydrolysis. Treatment of human umbilical vein endothelial cells ( HUVEC) with daunorubicin markedly decreased the mRNA expression and protein release of plasminogen activator inhibitor-1 (PAI-1). This cellular event was accompanied by a significant increase in the total ceramide content in HUVEC, On the other hand, tumor necrosis factor (TNF)-alpha treatment of HU VEC led to an increase in both PAI-I mRNA expression and protein release, a nd an enhancement of total ceramide content was also observed, The stimulat ing effect of TNF-alpha on PAI-I synthesis was attenuated by the pretreatme nt of HUVEC with daunorubicin. Interestingly, the daunorubicin-induced incr ease in ceramide content was blocked by addition of the potent ceramide syn thase inhibitor fumonisin B-1, while the TNF-alpha -induced ceramide increa se was not affected by this drug. Fumonisin B-1 treatment restored the daun orubicin-induced decrease in PAI-1 release to approximately 70% of the cont rol, but did not affect the TNF-alpha -induced increase in PAI-I release, T hus, these data imply the possibility that the subcellular topology of cera mide production determines its lipid mediator function ill the regulation o f PAI-I synthesis in HUVEC, because both TNF-alpha and daunorubicin could i ncrease the ceramide levels. (C) 2001 Elsevier Science B.V. All rights rese rved.