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Isovaleroylbinankadsurin A Ameliorates Cardiac Ischemia/Reperfusion Injury Through Activating GR Dependent RISK Signaling
44 Pages Posted: 4 Mar 2020
More...Abstract
Background: Ischemia/reperfusion (I/R) injury is a pathological process caused by reperfusion and thus prevention of I/R injury is of great significance to enhace the clinical efficacy on myocardial infarction patients. Isovaleroylbinankadsurin A (ISBA) has been demonstrated to possess multiple bioactivities for treating diseases. However, its protective effect on myocardial I/R injury remains unknown.
Methods: The cardiomyocytes hypoxia/reoxygantion (H/R) in vitro model and coronary artery ligation in vivo model were used to examine the protective effect of ISBA. Apoptosis was determined by flow cytometer and Caspase 3 activity. Protein level was determined by Western blot. The mitochondrial viability was examined with mitochondrial viability stain assay. Mitochondrial membrane potential was detected by JC-1 staining and reactive oxygen species (ROS) was stained with 2’,7’-dichlorodihydrofluorescein diacetate (DCF-DA). The binding interactions between ISBA and receptors was simulated by molecular docking.
Findings: ISBA effectively protected heart from I/R injury in in vitro and in vivo models. It remarkably blocked the apoptosis induced by H/R injury through mitochondrial dependent pathway, and the activation of reperfusion injury salvage kinase (RISK) pathway was demnstrated to be essential for ISBA to exert its protective effect on cardiomyocytes. Moreover, the result of the molecular docking exhibited that ISBA directly interacts with glucocorticoid receptor (GR) and its inhibitor RU486 could mostly counteract the protective effect of ISBA on cardiomyocytes. Most attractively, by activating GR dependent RISK pathway, ISBA significantly elevated the cellular anti-oxidative capacity and hence alleviated oxidative damage induced by I/R injury.
Interpretation: Our study proved that ISBA protected the heart from myocardial I/R injury through activating GR dependent RISK pathway and consequently inhibiting the ROS generation. It provides a valuable reference for ISBA to be developed as a candidate drug for cardiovascular diseases.
Funding Statement: This research was supported by the Macao Science and Technology Development Fund (FDCT) (Project No.: 062/2017/A2).
Declaration of Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Ethics Approval Statement: All animal experimental protocols were approved by the Animal Care and Use Committee of Control, Instituto para os Assuntos Cívicos e Municipais (IACM), Macao (AL072/DICV/SIS/2016).
Keywords: Kadsura coccinea; Isovaleroylbinankadsurin A; cardioprotection; mitochondria-dependent apoptosis; RISK pathway
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