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Published on: July 20, 2019
Mycophenolic acid attenuates tumor necrosis factor-alpha-induced endothelin-1 production in human aortic endothelial
Won Seok Yang1, Joo Mi Lee, Nam Jeong Han
1Division of Nephrology, Department of Internal Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea.
Insights
Mycophenolic acid (MPA) reduces tumor necrosis factor-alpha (TNF-alpha)-induced endothelin-1 (ET-1) production in aortic cells. This immunosuppressant targets pathways involved in atherosclerosis, suggesting a potential benefit for transplant recipients.
Area of Science:
- Cardiovascular Science
- Immunology
- Cell Biology
Background:
- Atherosclerotic cardiovascular disease is a primary cause of mortality in solid organ transplant recipients.
- Endothelin-1 (ET-1) plays a role in atherosclerosis development and is a potential therapeutic target.
- Mycophenolic acid (MPA) is an immunosuppressant used in transplant patients.
Purpose of the Study:
- To investigate the effect of MPA on tumor necrosis factor-alpha (TNF-alpha)-induced ET-1 production in human aortic endothelial cells.
Main Methods:
- Cultured human aortic endothelial cells were treated with TNF-alpha and MPA.
- Investigated the roles of transcription factors AP-1 and NF-kappaB, and signaling pathways including c-Jun NH2-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and reactive oxygen species (ROS).
- Utilized specific inhibitors for JNK (SP600125) and p38 MAPK (SB203580), and N-acetylcysteine (ROS scavenger).
Main Results:
- TNF-alpha increased ET-1 production via AP-1 and NF-kappaB, mediated by JNK and p38 MAPK, but not ERK.
- MPA attenuated TNF-alpha-induced ET-1 by reducing AP-1 and NF-kappaB DNA-binding activities.
- MPA inhibited JNK and p38 MAPK activations and ROS generation; effects on NF-kappaB and p65 phosphorylation were observed.
Conclusions:
- MPA mitigates TNF-alpha-induced ET-1 production through inhibition of ROS-dependent JNK and ROS-independent p38 MAPK.
- These pathways regulate NF-kappaB and AP-1, suggesting MPA's potential to ameliorate atherosclerosis in transplant recipients.
Aims:
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.
Methods And Results:
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.
Conclusion:
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.
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