title: Soluble receptor for advanced glycation end-products protects against ischemia/reperfusion-induced myocardial apoptosis via regulating the ubiquitin proteasome system.
abstract: Apoptosis participated in the pathological process of myocardial ischemia/reperfusion (I/R) injury. Previous studies have reported that endogenous substance sRAGE protect against I/R injury through inhibiting myocardial apoptosis. But the mechanisms are currently unknown. Prior work has demonstrated that ubiquitin proteasome system (UPS) dysfunction is closely related to apoptosis. We explored the potential role of UPS in the effect of sRAGE inhibition on I/R-induced myocardial apoptosis.
  
  
  
  Adult male C57BL mice treated with sRAGE (100μg/day, i.p.) or saline were performed to ligate left anterior descending coronary artery (LAD) as an in vivo model. As an in vitro model, primary murine cardiomyocytes pretreated with sRAGE or sRAGE-containing adenovirus were simulated I/R by "ischemia buffer". The TUNEL and caspase-3 activity were assessed. Also the activity and expression of proteasome were detected. sRAGE decreased the number of TUNEL-positive cardiomyocytes and caspase-3 activity, however, the inhibition of sRAGE on I/R-induced apoptosis was abolished by proteasome inhibitor Bortezimb (BTZ). sRAGE inhibited the decreased proteasome activity, also the reduction in protein and gene levels of β1i and β5i following I/R. Suppression of STAT3 blocked the inhibition of sRAGE on apoptosis induced by I/R. The chromatin immunoprecipitation (CHIP) results confirmed that sRAGE promoted activating STAT3 binding to β1i and β5i promoter.
  
  
  
  Our data suggest that the inhibition of sRAGE on I/R-induced apoptosis is associated with activation and expression of proteasome, including improved proteasome activity and elevated β1i and β5i expression mediated by STAT3 activation. We predict that sRAGE is a novel intervention to target UPS activation for preventing and treating myocardial apoptosis.
authors.affiliation: Department of Cardiology, Beijing Tian Tan Hospital, Capital Medical University, 6 Tiantan Xili, Dongcheng District, Beijing 100050, China. Electronic address: cxgbb@163.com.
authors.forename: Cai-Xia
authors.initials: CX
authors.lastname: Guo
authors.affiliation: Department of Cardiology, Beijing Tian Tan Hospital, Capital Medical University, 6 Tiantan Xili, Dongcheng District, Beijing 100050, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Physiology and Pathophysiology, Capital Medical University, Beijing 100069, China.
authors.forename: Xiang-Jun
authors.initials: XJ
authors.lastname: Zeng
authors.affiliation: Department of Physiology and Pathophysiology, Capital Medical University, Beijing 100069, China.
authors.forename: Hong-Xia
authors.initials: HX
authors.lastname: Wang
authors.affiliation: Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian 116011, China.
authors.forename: Hui-Hua
authors.initials: HH
authors.lastname: Li
authors.affiliation: Department of Cardiology, Department of Geriatrics, Beijing Tian Tan Hospital, Capital Medical University, Beijing 100050, China.
authors.forename: Feng-He
authors.initials: FH
authors.lastname: Du
authors.affiliation: Department of Cardiology, Beijing Tian Tan Hospital, Capital Medical University, 6 Tiantan Xili, Dongcheng District, Beijing 100050, China. Electronic address: chbux@126.com.
authors.forename: Bu-Xing
authors.initials: BX
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D000069286:Bortezomib / Q000008:administration & dosage; D053148:Caspase 3 / Q000235:genetics; D017127:Glycation End Products, Advanced / Q000008:administration & dosage* / Q000235:genetics; D006801:Humans; D051379:Mice; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000235:genetics*; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D050796:STAT3 Transcription Factor / Q000235:genetics*; D025801:Ubiquitin / Q000235:genetics
chemical_list: D017127:Glycation End Products, Advanced; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D025801:Ubiquitin; D000069286:Bortezomib; D053148:Caspase 3; D046988:Proteasome Endopeptidase Complex
keywords: Apoptosis; Myocardial Ischemia/reperfusion; STAT3; Ubiquitin proteasome system; sRAGE