The Cardioprotective Effect of Dexamethasone through Activation of RISK Pathway

Abstract

BackgroundTreatment of ischemic heart disease, mainly focuses on returning blood flow back to the ischemic area. However, irreversible cell damage caused by reperfusion is the main risk of these approaches. The reperfusion injury salvage kinase (RISK) pathway can be targeted to decrease cell death and restore cell function during ischemia/reperfusion (I/R). Glucocorticoids are part of the feedback mechanism in the immune system that inhibits inflammation. Their intracellular effect is mediated by binding to the glucocorticoid receptor (GR). Dexamethasone(DEX) is a corticosteroid medicine used for anti‐inflammation which has a higher affinity to the GR than cortisol.MethodsThe effects of DEX was studied in an acute I/R injury model in which the left anterior descending coronary artery was occluded. Ex vivo mouse heart perfusion Langendorff system was used to measure the effects on glucose receptor 4 (GLUT4) translocation.Results‐Significant recovery of cardiac function was observed following DEX pretreatment during I/R injury. DEX activated the protective RISK pathways (includes ERK, AKT, and AMPK) significantly in a time and dose dependent manner. Furthermore, AMPK's translocation into nucleus was found after DEX treatment compared with I/R only. To deeply investigate the reason of AMPK translocation, immunoprecipitation was conducted. Results showed GR could interact with AMPK and recruit Sestrin 2‐LKB1 complex during I/R, which helped AMPK's phosphorylation and translocation during I/R. Moreover, one of AMPK's downstream effects ‐ stimulating GLUT4′s translocation to cell surface ‐ was also triggered after DEX stimulation.ConclusionDEX's cardioprotective function is achieved by activating the RISK protective signaling pathways during I/R.