Ginkgolide K protects the heart against ER stress injury by activating the IRE1α/XBP1 pathway

OBJECTIVE Here we investigated the effects and the underlying mechanism of Ginkgolide K(1,10-dihydroxy-3,14-didehydroginkgolide,GK)on cardiac ER stress.METHODS Cell death,apoptosis,and ER stressrelated signalling pathwayswere measuredin cultured neonatal rat cardiomyocytes(NRCMs),treated with the ER stress inducers tunicamycin,hydrogen peroxide,and thapsigargin.Acute myocardial infarction was established using left coronary artery occlusion in mice,and infarct size was measured by triphenyltetrazolium chloride(TTC)staining.Echocardiography was used to assess heart function and transmission electron microscopy for evaluating ER expansion.RESULTS GK significantly decreased ER stress-induced cell death in both in vitro and in vivomodels.In ischemic injured mice,GK treatment reduced infarct size,rescued heart dysfunction and ameliorated ER dilation.Mechanistic studies revealed that the beneficial effects of GK occur through enhancement of inositol-requiring enzyme 1α(IRE1α)/X box-binding protein-1(XBP1)activity,which in turn leads to increased ER-associated degradation(ERAD)-mediated clearance of misfolded proteins and autophagy.In addition,GK is also able to partially repress the pro-apoptotic action of regulated IRE1-dependent decay(RIDD)and JNK pathway.CONCLUSION GK acts through selective activation of the IRE1α/XBP1 pathway to limit ER stress injury.GK is revealed as a promising therapeutic agent to ameliorate ER stress for treating cardiovascular diseases.