Isoform-specific functions of c-Jun N-terminal kinase 1 and 2 in lung ischemia-reperfusion injury through the c-Jun/activator protein-1 pathway
Autor: | Linlin Wang, Xian-zhang Zeng, Xiaoguang Cui, Wei Gao, Jing Tan, Wanchao Yang |
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Rok vydání: | 2021 |
Předmět: |
Pulmonary and Respiratory Medicine
Small interfering RNA Proto-Oncogene Proteins c-jun Apoptosis 030204 cardiovascular system & hematology Pharmacology Nitric oxide Small hairpin RNA 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine medicine Animals Mitogen-Activated Protein Kinase 9 Mitogen-Activated Protein Kinase 8 Phosphorylation Lung Cells Cultured biology Kinase business.industry c-jun Endothelial Cells medicine.disease Rats Isoenzymes Transcription Factor AP-1 Nitric oxide synthase Transplantation Disease Models Animal 030228 respiratory system chemistry Reperfusion Injury Microvessels biology.protein Cytokines Surgery Inflammation Mediators Cardiology and Cardiovascular Medicine business Reperfusion injury Lung Transplantation Signal Transduction |
Zdroj: | The Journal of Thoracic and Cardiovascular Surgery. 162:e143-e156 |
ISSN: | 0022-5223 |
Popis: | Background: c-Jun N-terminal kinase 1 (JNK1) and JNK2 regulate distinct pathological processes in lung diseases. Here we discriminated the respective roles of these kinases in lung transplantation-induced ischemia-reperfusion injury (IRI). Methods Rat pulmonary microvascular endothelial cells were transfected with JNK1 small-interfering RNA (siRNA) and JNK2 siRNA and then subjected to in vitro IRI. For the isoform confirmed to aggravate IRI, the delivery of short-hairpin RNA (shRNA) plasmid was performed by intratracheal administration 48 hours before transplantation into donor rats. After a 3-hour reperfusion, the samples were collected. Results JNK1 siRNA decreased but JNK2 siRNA increased JNK phosphorylation and activity, phosphorylated and total c-Jun, and activator protein-1 activity. Although JNK1 siRNA decreased apoptosis and the levels of malondialdehyde, interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF-α), it increased the levels of superoxide dismutase, S-phase percentage, and cyclin D1; JNK2 siRNA had a converse effect. JNK1 siRNA decreased the level of lactate dehydrogenase and increased the levels of VE-cadherin, nitric oxide, phosphorylated nitric oxide synthase, and cell viability; JNK2 si RNA had a converse effect. Compared with the control group, the JNK1 shRNA group exhibited a higher lung oxygenation index and lower lung apoptosis index, injury score, wet weight:dry weight ratio, and levels of IL-1, IL-6, and TNF-α. Conclusions JNK1 aggravated, but JNK2 alleviated, IRI through differential regulation of the JNK1 pathway in in vitro ischemia-reperfusion. JNK1 silence attenuated lung graft dysfunction by inhibiting inflammation and apoptosis. These findings provide a theoretical basis for devising therapeutic strategies against IRI after lung transplantation. |
Databáze: | OpenAIRE |
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