Ginkgolide K protects the heart against endoplasmic reticulum stress injury by activating the inositol-requiring enzyme 1α/X box-binding protein-1 pathway

BACKGROUND AND PURPOSE Endoplasmic reticulum (ER) stress is increasingly recognized as an important causal factor of many diseases. Targeting ER stress has now emerged as a new therapeutic strategy for treating cardiovascular diseases. Here we investigated the effects and the underlying mechanism of Ginkgolide K (1,10-dihydroxy-3,14-didehydroginkgolide, GK) on cardiac ER stress. EXPERIMENTAL APPROACH Cell death, apoptosis, and ER stress-related signalling pathways were measured in 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. KEY RESULTS GK significantly decreased ER stress-induced cell death in both in vitro and in vivo models. 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 occurred through enhancement of inositol-requiring enzyme 1α (IRE1α)/ X box-binding protein-1 (XBP1) activity, which in turn led to increased ER-associated degradation (ERAD)- mediated clearance of misfolded proteins and autophagy. In addition, GK was also able to partially repress the pro-apoptotic action of regulated IRE1-dependent decay (RIDD) and JNK pathway. CONCLUSIONS AND IMPLICATIONS In 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. This