Signal transduction pathways involved in cytokine stimulation of endothelin-1 release from human vascular smooth muscle cells

Endothelin-l (ET-I) mRNA expression and peptide production in human vascula r smooth muscle cells (HVSMCs) are markedly increased by exposure to cytoki nes. As the transcription factor nuclear factor-kappaB (NF-kappaB) often me diates the effects of cytokines in target cells the aim of this study was t o determine whether the production of ET-1 following exposure of HVSMCs to cytokines depends upon activation of NF-kappaB. BAY 11-7082, an inhibitor o f cytokine-induced inhibitor protein (I kappaB) phosphorylation, inhibited cytokine-stimulated upregulation of preproendothelin-1 InRNA expression and ET-1 peptide production. In addition, immunoblotting showed that cytokine stimulation of ET-1 release in VSMCs involves nuclear translocation of NF-k appaB. In conclusion, NF-kappaB activation is involved in the stimulation b y cytokines of ET-1 release from HVSMCs. As upregulated production of ET-1 within VSMCs may underlie the causative role of ET-1 in a number of disease states this finding indicates that NF-kappaB within HVSMCs could be centra l to a number of vascular pathologies.