title: Effect of tacrolimus on myocardial infarction is associated with inflammation, ROS, MAP kinase and Akt pathways in mini-pigs.
abstract: OBJECTIVE
  This study tested the hypothesis that tacrolimus therapy limited left ventricular (LV) infarct and remodeling by suppressing the inflammatory response, oxidative stress and regulating the mitogen-activated protein kinase (MAPK) and Akt signaling pathways in an acute myocardial infarction (AMI) mini-pig model by ligating the left anterior descending coronary artery (LAD).
  
  
  METHODS
  Twelve male mini-pigs were equally randomized into AMI treated by saline (3.0 mL) (AMI(S)), and AMI treated by tacrolimus (0.5 mg) (AMI(T)). Thirty minutes after the procedure, intra-LAD injections were performed just beyond the ligation.
  
  
  RESULTS
  Inflammatory biomarkers at transcription or protein levels [matrix metalloproteinase (MMP9), plasminogen activator inhitor-1, tumor necrotic factor (TNF-α), nuclear factor (NF)-κB] and the cellular level (CD40+ cells) were markedly higher in AMI(S) than in AMI(T) animals (all p<0.001). Fibrosis biomarkers at the protein level (α-smooth muscle actin, transforming growth factor-β) and Sirius-red staining were notably higher in AMI(S) than in AMI(T) animals (all p<0.03). Antioxidant biomarkers at protein or transcription levels (heme oxygenase-1, quinone oxidoreductase-1, glutathione reductase, glutathione peroxidase) were significantly higher in AMI(S) than in AMI(T) animals (all p<0.01). Protein expressions of ERK1, p38 MAPK and Akt were markedly increased in AMI(S) compared to AMI(T) animals (all p<0.001). Significantly aggravated LV infarction and remodeling were noted in AMI(S) compared to AMI(T) animals, whereas LV ejection fraction was markedly decreased in AMI(S) compared to AMI(T) animals (all p<0.001).
  
  
  CONCLUSIONS
  Intra-coronary administration of tacrolimus attenuated inflammation and MAPK signaling, limited infarct size, and preserved LV function.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Cheng-Hsu
authors.initials: CH
authors.lastname: Yang
authors.forename: Jiunn-Jye
authors.initials: JJ
authors.lastname: Sheu
authors.forename: Tzu-Hsien
authors.initials: TH
authors.lastname: Tsai
authors.forename: Sarah
authors.initials: S
authors.lastname: Chua
authors.forename: Li-Teh
authors.initials: LT
authors.lastname: Chang
authors.forename: Hsueh-Wen
authors.initials: HW
authors.lastname: Chang
authors.forename: Fan-Yen
authors.initials: FY
authors.lastname: Lee
authors.forename: Yung-Lung
authors.initials: YL
authors.lastname: Chen
authors.forename: Sheng-Ying
authors.initials: SY
authors.lastname: Chung
authors.forename: Cheuk-Kwan
authors.initials: CK
authors.lastname: Sun
authors.forename: Steve
authors.initials: S
authors.lastname: Leu
authors.forename: Chia-Hung
authors.initials: CH
authors.lastname: Yen
authors.forename: Hon-Kan
authors.initials: HK
authors.lastname: Yip
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D004195:Disease Models, Animal; D004452:Echocardiography; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007249:Inflammation / Q000503:physiopathology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009203:Myocardial Infarction / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology*; D018384:Oxidative Stress; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013552:Swine; D013556:Swine, Miniature; D016559:Tacrolimus / Q000494:pharmacology*
chemical_list: D015415:Biomarkers; D007166:Immunosuppressive Agents; D017382:Reactive Oxygen Species; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D016559:Tacrolimus