Fibrauretine reduces ischemia/reperfusion injury via RISK/eNOS activation
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Current studies have shown that fibrauretine can be used in the treatment of cardiovascular diseases; however, the protective mechanism of fibrauretine in cardiovascular diseases is unclear. The aim of this study was to investigate the effect and mechanism of fibrauretine in acute myocardial ischemia-reperfusion injury. We investigated the effects of glucocorticoid receptor/oestrogen receptor (GR/ER)-mediated Akt phosphorylation, extracellular regulated protein kinase (ERK1/2) activation and nitric oxide (NO) on the treatment of acute myocardial ischemia-reperfusion injury by fibrauretine. Myocardial ischemia-reperfusion (I/R) injury models were established in rats and gene-knockout mice, and the infarct size was measured. We detected the expression and phosphorylation of phosphatidylinositol-3 kinase (PI3K), protein kinase B (Akt), glucocorticoid receptor, oestrogen receptor, lactate dehydrogenase (LDH), creatine phosphokinase (CK-MB), stress-activated protein kinase (JNK), P38 protein kinase (P38 MAPK) and nitric oxide synthase (NOS) with or without the inhibitors to investigate the protective effect of fibrauretine on the heart. The results showed that fibrauretine can significantly reduce the myocardial infarction area in myocardial I/R injury, inhibit the activities of LDH and CK-MB in the serum, and increase the content of NO. However, the effects of fibrauretine on the reduction of the myocardial infarction area were eliminated by the PI3K inhibitor LY294002, Akt inhibitor IV, GR inhibitor RU468, ER inhibitor tamoxifen, eNOS inhibitor L-NAME and ERK1/2 inhibitor U0126. Moreover, in the case of WT mice and gene-knockout eNOS and iNOS mice, fibrauretine was able to significantly reduce the myocardial infarction area in iNOS−/− and wild type mice. However, there was no significant protective effect of fibrauretine in eNOS−/− mice. It is suggested that eNOS plays an important role in the protective effect of fibrauretine on the heart. Therefore, the results of this study show that the protective effect of fibrauretine on myocardial I/R injury is closely associated with eNOS expression, GR/ER-induced Akt phosphorylation and ERK1/2 activation.
KeywordsFibrauretine Endothelial nitric oxide synthase RISK pathway Ischemia-reperfusion
All the authors had full access to all the data in the study and take responsibility for the integrity of the data and accuracy of the data analysis. YWZ and GG were responsible for the study concept and design. CSW and RC contributed to the acquisition of data. YWZ and XL assisted with data analysis and the interpretation of findings. CSW drafted the manuscript. YWZ and GG provided critical revisions of the manuscript for important intellectual content, obtained funding and supervised the study. All the authors approved the final version for publication.
This work was supported by the Shenzhen Science and Technology Project (JCYJ20180306172459580).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflicts of interest.
The submitted manuscript involved animal research. All procedures adhered to the National Institutes of Health Guide for the Care and Use of Laboratory Animals. The experiment was performed in compliance with the National Institutes of Health and institutional guidelines for the humane care of animals.
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