title: Sodium tanshinone IIA sulfonate ameliorates ischemia-induced myocardial inflammation and lipid accumulation in Beagle dogs through NLRP3 inflammasome.
abstract: BACKGROUND
  The activation of NOD-like receptor (NLR) family, pyrin-domain containing 3 (NLRP3) inflammasome has now been proven to have a close connection with myocardial ischemia (MI) during acute phase, but the mechanisms are not completely clear. This study investigated the role of NLRP3 inflammasome in pathogenesis of MI injury including inflammation and lipid accumulation, as well as the effects of sodium tanshinone IIA sulfonate (STS) and diltiazem hydrochloride (DI).
  
  
  METHODS
  Occlusion of left anterior descending (LAD) in canines was employed to induce MI. STS and DI were given intravenously 15 min after LAD occlusion. Cardiac function, inflammation and lipid levels, as well as related signaling pathways were determined.
  
  
  RESULTS
  MI induced in Beagle dog was characterized by elevated ST-segment and increased CK-MB level in serum. Cardiac NLRP3 inflammasome was activated with elevated myocardial IL-1β and IL-18 concentrations mediated by ROS over-production and TXNIP over-expression in MI dogs. Additionally, pro-inflammatory cytokines induced impairment of cardiac JAK2-STAT3 inflammatory pathway and insulin signaling pathway in this model, resulting in down-regulation of cardiac PPAR-α expression, subsequently causing lipid metabolism disorders characterized by elevation of myocardial lipid concentrations. These abnormalities were attenuated by the treatment of STS and DI.
  
  
  CONCLUSIONS
  These data firstly demonstrated that cardiac NLRP3 inflammasome activation driven by cardiac ROS over-production and TXNIP up-expression resulted in impairment of the JAK2-STAT3 and insulin signaling pathways, leading to disorder of lipid metabolism in myocardial ischemic dogs through PPAR-α over-expression. STS and DI might target cardiac NLRP3 inflammasome in preventing MI injury.
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China; School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Hu
authors.affiliation: School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Bo
authors.initials: B
authors.lastname: Wei
authors.affiliation: School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Linlin
authors.initials: L
authors.lastname: Wei
authors.affiliation: School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Kai
authors.initials: K
authors.lastname: Hua
authors.affiliation: School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Xing
authors.initials: X
authors.lastname: Yu
authors.affiliation: College of Pharmaceutical Science, Soochow University, Suzhou 215123, PR China.
authors.forename: Huanqiu
authors.initials: H
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China; School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: chinacpu1001@163.com.
authors.forename: Hui
authors.initials: H
authors.lastname: Ji
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D002352:Carrier Proteins / Q000378:metabolism*; D054059:Coronary Occlusion / Q000473:pathology; D003331:Coronary Vessels / Q000601:surgery; D052279:Creatine Kinase, MB Form / Q000097:blood; D004195:Disease Models, Animal; D004285:Dogs; D004365:Drugs, Chinese Herbal / Q000627:therapeutic use*; D004562:Electrocardiography; D058847:Inflammasomes / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects*; D008297:Male; D017202:Myocardial Ischemia / Q000378:metabolism / Q000517:prevention & control*; D047493:PPAR alpha / Q000378:metabolism; D010616:Phenanthrenes / Q000627:therapeutic use*; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D015415:Biomarkers; D002352:Carrier Proteins; D004365:Drugs, Chinese Herbal; D058847:Inflammasomes; D047493:PPAR alpha; D010616:Phenanthrenes; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; C024894:tanshinone II A sodium sulfonate; D053614:Janus Kinase 2; D052279:Creatine Kinase, MB Form
keywords: Insulin signaling pathway; JAK2–STAT3 inflammatory pathway; MI injury; NLRP3; PPAR-α