Division of Nephrology, Department of Internal Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea.
Atherosclerosis. 2010 Jul;211(1):48-54. doi: 10.1016/j.atherosclerosis.2010.01.018. Epub 2010 Jan 25.
Atherosclerotic 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-alpha (TNF-alpha)-induced ET-1 production in aortic endothelial cells.
In cultured human aortic endothelial cells, TNF-alpha increased ET-1 through AP-1 and NF-kappaB, whereas MPA attenuated it by reducing both AP-1 and NF-kappaB DNA-binding activities. TNF-alpha 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-alpha-induced reactive oxygen species (ROS) inhibited JNK activation, but not p38 MAPK. N-acetylcysteine, SP600125 (JNK inhibitor) and SB203580 (p38 MAPK inhibitor) attenuated TNF-alpha-induced DNA-binding activities of both AP-1 and NF-kappaB. MPA inhibited JNK and p38 MAPK activations as well as ROS generation. N-acetylcysteine, SP600125, SB203580 and MPA had no effect on either TNF-alpha-induced IkappaBalpha degradation or p65 nuclear translocation, but attenuated p65 Ser276 phosphorylation.
MPA attenuated TNF-alpha-induced ET-1 production through inhibitions of ROS-dependent JNK and ROS-independent p38 MAPK that regulated NF-kappaB as well as AP-1. These findings suggest that MPA could have an effect of amelioration of atherosclerosis.
动脉粥样硬化性心血管疾病是实体器官移植受者发病率和死亡率的主要原因。内皮素-1（ET-1）参与动脉粥样硬化的发病机制，是潜在的治疗靶点之一。本研究旨在评估免疫抑制剂霉酚酸（MPA）对肿瘤坏死因子-α（TNF-α）诱导的人主动脉内皮细胞 ET-1 产生的影响。
在培养的人主动脉内皮细胞中，TNF-α通过 AP-1 和 NF-κB 增加 ET-1，而 MPA 通过降低 AP-1 和 NF-κB 的 DNA 结合活性来减弱其作用。TNF-α通过 c-Jun NH2-末端激酶（JNK）和 p38 丝裂原活化蛋白激酶（MAPK）增加 ET-1，但不通过细胞外信号调节激酶。下调 TNF-α诱导的活性氧（ROS）的 N-乙酰半胱氨酸抑制 JNK 激活，但不抑制 p38 MAPK。N-乙酰半胱氨酸、SP600125（JNK 抑制剂）和 SB203580（p38 MAPK 抑制剂）减弱了 TNF-α诱导的 AP-1 和 NF-κB 的 DNA 结合活性。MPA 抑制 JNK 和 p38 MAPK 的激活以及 ROS 的产生。N-乙酰半胱氨酸、SP600125、SB203580 和 MPA 对 TNF-α诱导的 IkappaBalpha 降解或 p65 核易位没有影响，但减弱了 p65 Ser276 磷酸化。
MPA 通过抑制 ROS 依赖性 JNK 和 ROS 非依赖性 p38 MAPK 减弱 TNF-α诱导的 ET-1 产生，从而调节 NF-κB 以及 AP-1。这些发现表明 MPA 可能对动脉粥样硬化的改善有作用。
