Mycophenolic acid attenuates tumor necrosis factor-α-induced endothelin-1 production in human aortic endothelial cells

Abstract

AimsAtherosclerotic cardiovascular disease is the major cause of morbidity and mortality in solid organ transplant recipients. Endothelin-1 (ET-1) is implicated in the pathogenesis of atherosclerosis and is one of the potential therapeutic targets. This study was conducted to evaluate the effect of mycophenolic acid (MPA), an immunosuppressant for the transplant recipients, on tumor necrosis factor-α (TNF-α)-induced ET-1 production in aortic endothelial cells. Methods and resultsIn cultured human aortic endothelial cells, TNF-α increased ET-1 through AP-1 and NF-κB, whereas MPA attenuated it by reducing both AP-1 and NF-κB DNA-binding activities. TNF-α increased ET-1 via c-Jun NH2-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK), but not extracellular signal-regulated kinase. N-acetylcysteine that downregulated TNF-α-induced reactive oxygen species (ROS) inhibited JNK activation, but not p38 MAPK. N-acetylcysteine, SP600125 (JNK inhibitor) and SB203580 (p38 MAPK inhibitor) attenuated TNF-α-induced DNA-binding activities of both AP-1 and NF-κB. MPA inhibited JNK and p38 MAPK activations as well as ROS generation. N-acetylcysteine, SP600125, SB203580 and MPA had no effect on either TNF-α-induced IκBα degradation or p65 nuclear translocation, but attenuated p65 Ser276 phosphorylation. ConclusionMPA attenuated TNF-α-induced ET-1 production through inhibitions of ROS-dependent JNK and ROS-independent p38 MAPK that regulated NF-κB as well as AP-1. These findings suggest that MPA could have an effect of amelioration of atherosclerosis.