title: Fasudil protects the heart against ischemia-reperfusion injury by attenuating endoplasmic reticulum stress and modulating SERCA activity: the differential role for PI3K/Akt and JAK2/STAT3 signaling pathways.
abstract: Disordered calcium homeostasis can lead to endoplasmic reticulum (ER) stress. Our previous data showed that time course activation of ER stress contributes to time-related increase in ischemia-reperfusion (I/R) injury. However, it has not been tested whether PI3K/Akt and JAK2/STAT3 pathways play differential roles in reducing ER stress to protect the heart. In the present study, using fasudil which is a specific inhibitor of ROCK, we aimed to investigate whether improved SERCA expression and activity accounts for reduced ER stress by ROCK inhibition, specifically whether PI3K/Akt and JAK2/STAT3 pathways are differentially involved in modulating SERCA activity to reduce ER stress and hence I/R injury. The results showed that during the reperfusion period following 45 min of coronary ligation the infarct size (IS) increased from 3 h of reperfusion (45.4±5.57%) to 24 h reperfusion (64.21±5.43, P<0.05), which was associated with ER stress dependent apoptosis signaling activation including CHOP, Caspase-12 and JNK (P<0.05, respectively).The dynamic ER stress activation was also related to impaired SERCA activity at 24 h of reperfusion. Administration of fasudil at 10 mg/Kg significantly attenuated ROCK activation during reperfusion and resulted in an improved SERCA activity which was closely associated with decreases in temporal activation of ER stress and IS changes. Interestingly, while both PI3K/Akt and JAK2/STAT3 signaling pathways played equal role in the protection offered by ROCK inhibition at 3 h of reperfusion, the rescued SERCA expression and activity at 24 h of reperfusion by fasudil was mainly due to JAK2/STAT3 activation, in which PI3K/Akt signaling shared much less roles.
authors.affiliation: Division of Cardiology, Shanghai Sixth Hospital, Shanghai Jiao Tong University School of Medicine, State Key Discipline Division, Shanghai, People's of Republic of China.
authors.forename: Yapeng
authors.initials: Y
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.forename: Jianping
authors.initials: J
authors.lastname: Tao
authors.forename: Ping
authors.initials: P
authors.lastname: Xin
authors.forename: Mingya
authors.initials: M
authors.lastname: Liu
authors.forename: Jingbo
authors.initials: J
authors.lastname: Li
authors.forename: Meng
authors.initials: M
authors.lastname: Wei
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D053454:Caspase 12 / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006360:Heat-Shock Proteins / Q000378:metabolism; D053614:Janus Kinase 2 / Q000378:metabolism; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D020033:Protein Isoforms / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D002316:Cardiotonic Agents; D053454:Caspase 12; D002867:Chromones; D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D053614:Janus Kinase 2; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D020033:Protein Isoforms; D051057:Proto-Oncogene Proteins c-akt; D050796:STAT3 Transcription Factor; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D014157:Transcription Factors; D054460:rho-Associated Kinases; C506948:Atp2a2 protein, rat; C506951:Atp2a3 protein, rat; C513243:Etv5 protein, rat; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP; C494088:Stat3 protein, rat; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C507927:Jak2 protein, rat; C506443:Casp12 protein, rat; C049347:fasudil