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

Abstract

*These two authors contributed equally to this work. BACKGROUND AND PURPOSEEndoplasmic 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. EXPERIMENTAL APPROACHCell 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. KEY RESULTSGinkgolide 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. CONCLUSIONS AND IMPLICATIONSIn 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. AbbreviationsASK1, apoptotic signalling kinase-1; ATF4, activating transcription factor 4; ATF6, activating transcription factor 6; CHOP, C/EBP homologous protein; ER, endoplasmic reticulum; ERAD, ER-associated degradation; eIF2α, eukaryotic translation initiation factor 2α; GB, ginkgolide B; GK, ginkgolide K; GRP78, glucose-regulated protein 78 kD; IRE1α, inositol-requiring enzyme 1α; NRCMs, neonatal rat cardiomyocytes; PERK, pancreatic eIF2α kinase; RIDD, regulated IRE1-dependent decay; TRAF2, TNF receptor-associated factor 2; UPR, unfolded protein response; XBP1, X box-binding protein-1 BJP IntroductionThe endoplasmic reticulum (ER) is a membranous organelle that plays an important role in the maintenance of cellular processes such as protein processing, calcium homeostasis and lipid biosynthesis. Effective ER function is essential for the folding of secretory and membrane proteins (Wei and Hendershot, 1996). A number of cellular stresses disturb the balance between the folding capacity of the ER and the burden of incoming proteins, including oxidative stress, ischaemic insult, abnormal ER calcium content, and enhanced expression of normal and/or folding-defective proteins. These events lead to the accumulation of unfo...

Endoplasmic reticulum stress in the heart: insights into mechanisms and drug targets

“…However, in patients with previous history of hypertension and heart disease, sunitinib appears to increase the risk for cardiovascular disease (Chu et al, ). Recently, Ginkgolide K (1,10‐dihydroxy‐3,14‐didehydroginkgolide, GK), a diterpene lactone isolated from the leaves of Ginkgo biloba , has been demonstrated to protect cardiomyocytes from ER stress‐induced apoptosis both in vitro and in vivo (Wang et al, ). In response to ER stress, GK can selectively activate the IRE1α/XBP1 pathway and inhibit the activation of RIDD and JNK (Wang et al, ).…”

“…Recently, Ginkgolide K (1,10‐dihydroxy‐3,14‐didehydroginkgolide, GK), a diterpene lactone isolated from the leaves of Ginkgo biloba , has been demonstrated to protect cardiomyocytes from ER stress‐induced apoptosis both in vitro and in vivo (Wang et al, ). In response to ER stress, GK can selectively activate the IRE1α/XBP1 pathway and inhibit the activation of RIDD and JNK (Wang et al, ). Therefore, GK has a potential for treating cardiovascular diseases.…”

Comparing the role of Ginkgolide B and Ginkgolide K on cultured astrocytes exposed to oxygen‑glucose deprivation

“…GK has been reported to exhibit protective effects against glutamate cytotoxicity and H 2 O 2 -induced cytotoxicity in PC12 cells ( 21 , 22 ). GK also protects the heart against endoplasmic reticulum stress by activating the inositol-requiring enzyme 1a/X box-binding protein-1 pathway ( 23 ), and against acute ischemic stroke caused by MCAO through antioxidative effects ( 24 ). To the best of our knowledge, there has been no comparative study of GB and GK or a study examining the role of GK on astrocytes exposed to oxygen-glucose deprivation (OGD).…”

Roles of Autophagy in Ischemic Heart Diseases and the Modulatory Effects of Chinese Herbal Medicine

“…Ginkgolide K (GK) is an extract isolated from the leaves of Ginkgo biloba, which is another traditional herb widely used for cardiovascular diseases. A study reported by Wang et al (2016c) indicated that GK enhanced autophagic flux by increasing the expression of Beclin-1 and LCB in Tunicamycin treated neonatal rat cardiomyocytes, and demonstrated cardioprotective effects. However, the exact mechanism by which GK boosts the autophagic response remains unclear.…”