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Targeting ER stress has now emerged as a new therapeutic strategy for treating cardiovascular diseases. Here, we investigated the effects and underlying mechanism of ginkgolide K (1,10\u2010dihydroxy\u20103,14\u2010didehydroginkgolide, GK) on cardiac ER stress.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Cell death, apoptosis and ER stress\u2010related signalling pathways were measured in cultured neonatal rat cardiomyocytes, 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 staining. Echocardiography was used to assess heart function and transmission electron microscopy for evaluating ER expansion.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Ginkgolide K (GK) significantly decreased ER stress\u2010induced cell death in both <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> models. In ischaemic 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\u2010requiring enzyme 1\u03b1 (IRE1\u03b1)\/X box\u2010binding protein\u20101 (XBP1) activity, which in turn led to increased ER\u2010associated degradation\u2010mediated clearance of misfolded proteins and autophagy. In addition, GK was also able to partly repress the pro\u2010apoptotic action of regulated IRE1\u2010dependent decay and JNK pathway.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>In conclusion, GK acts through selective activation of the IRE1\u03b1\/XBP1 pathway to limit ER stress injury. GK is revealed as a promising therapeutic agent to ameliorate ER stress for treating cardiovascular diseases.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.13516","type":"journal-article","created":{"date-parts":[[2016,5,17]],"date-time":"2016-05-17T23:44:59Z","timestamp":1463528699000},"page":"2402-2418","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":61,"title":["Ginkgolide K protects the heart against endoplasmic reticulum stress injury by activating the inositol\u2010requiring enzyme 1\u03b1\/X box\u2010binding protein\u20101 pathway"],"prefix":"10.1111","volume":"173","author":[{"given":"Shoubao","family":"Wang","sequence":"first","affiliation":[{"name":"Faculty of Life Sciences The University of Manchester  Manchester UK"},{"name":"Beijing Key Laboratory of Drug Targets Identification and Drug Screening Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College  Beijing 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