Effect of tacrolimus on myocardial infarction is associated with inflammation, ROS, MAP kinase and Akt pathways in mini-pigs

J Atheroscler Thromb. 2013;20(1):9-22. doi: 10.5551/jat.14316. Epub 2012 Aug 16.

Abstract

Aim: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Blotting, Western
  • Disease Models, Animal
  • Echocardiography
  • Immunohistochemistry
  • Immunosuppressive Agents / pharmacology*
  • Inflammation / physiopathology*
  • Mitogen-Activated Protein Kinases / metabolism*
  • Myocardial Infarction / enzymology
  • Myocardial Infarction / metabolism
  • Myocardial Infarction / physiopathology*
  • Oxidative Stress
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Reactive Oxygen Species / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Swine
  • Swine, Miniature
  • Tacrolimus / pharmacology*

Substances

  • Biomarkers
  • Immunosuppressive Agents
  • Reactive Oxygen Species
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinases
  • Tacrolimus