title: Ginkgolide K protects the heart against endoplasmic reticulum stress injury by activating the inositol-requiring enzyme 1α/X box-binding protein-1 pathway.
abstract: 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 underlying mechanism of ginkgolide K (1,10-dihydroxy-3,14-didehydroginkgolide, GK) on cardiac ER stress.
  
  
  
  Cell death, apoptosis and ER stress-related 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.
  
  
  
  Ginkgolide K (GK) significantly decreased ER stress-induced cell death in both in vitro and in vivo 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-requiring enzyme 1α (IRE1α)/X box-binding protein-1 (XBP1) activity, which in turn led to increased ER-associated degradation-mediated clearance of misfolded proteins and autophagy. In addition, GK was also able to partly repress the pro-apoptotic action of regulated IRE1-dependent decay and JNK pathway.
  
  
  
  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.
authors.affiliation: Faculty of Life Sciences, The University of Manchester, Manchester, UK.|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, China.
authors.forename: Shoubao
authors.initials: S
authors.lastname: Wang
authors.affiliation: State Key Laboratory of New-tech for Chinese Medicine Pharmaceutical Process, Lianyungang, China.
authors.forename: Zhenzhong
authors.initials: Z
authors.lastname: Wang
authors.affiliation: State Key Laboratory of New-tech for Chinese Medicine Pharmaceutical Process, Lianyungang, China.|Faculty of Life Science and Technology, China Pharmaceutical University, Nanjing, China.
authors.forename: Qiru
authors.initials: Q
authors.lastname: Fan
authors.affiliation: Faculty of Life Sciences, The University of Manchester, Manchester, UK.
authors.forename: Jing
authors.initials: J
authors.lastname: Guo
authors.affiliation: Faculty of Life Sciences, The University of Manchester, Manchester, UK.
authors.forename: Gina
authors.initials: G
authors.lastname: Galli
authors.affiliation: 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, China.
authors.forename: Guanhua
authors.initials: G
authors.lastname: Du
authors.affiliation: Faculty of Life Sciences, The University of Manchester, Manchester, UK.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of New-tech for Chinese Medicine Pharmaceutical Process, Lianyungang, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xiao
mesh_terms: D017398:Alternative Splicing / Q000187:drug effects; D000818:Animals; D004305:Dose-Response Relationship, Drug; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004722:Endoribonucleases / Q000378:metabolism*; D046934:Ginkgolides / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D007783:Lactones / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009206:Myocardium / Q000166:cytology / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D000071717:X-Box Binding Protein 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D046934:Ginkgolides; D007783:Lactones; D012333:RNA, Messenger; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; C481151:ginkgolide K; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases