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Cathepsin B inhibition attenuates cardiac dysfunction and remodeling following myocardial infarction by inhibiting the NLRP3 pathway.

Abstract
Recently, cathepsin B has been demonstrated to be involved in myocardial infarction (MI). This study aimed to elucidate the effects of a specific cathepsin B inhibitor, CA-074Me, on cardiac dysfunction, remodeling and fibrosis following MI in a rat model. Furthermore, the potential mechanisms of action of this inhibitor were investigated. In the present study, Sprague-Dawley rats were anesthetized and subjected to a sham operation or left anterior descending coronary artery ligation, followed by intraperitoneal injection of CA-074Me (10 mg/kg/day) or an equal volume of vehicle for 4 weeks. Activation of the cathepsin B and NLRP3 pathway was detected. Cardiac function was assessed by echocardiography, while hypertrophy and fibrosis were determined by Masson's trichrome, immunofluorescence and morphometry. The results demonstrated that cathepsin B-NLRP3 activation was inhibited by CA-074Me treatment. Following such treatment for 4 weeks, the rats demonstrated smaller decreases in cardiac function, and a decrease in cardiomyocyte hypertrophy and the level of fibrosis. Cathepsin B inhibition significantly attenuated cardiac dysfunction, and reduced cardiomyocyte size and cardiac fibrosis in the experimental MI model, by inhibiting NLRP3 activation. This suggested that targeting the cathepsin B-NLRP3 pathway may represent a novel therapeutic strategy to prevent heart failure and remodeling following MI.
AuthorsAiguo Liu, Xuan Gao, Qingbin Zhang, Lianqun Cui
JournalMolecular medicine reports (Mol Med Rep) Vol. 8 Issue 2 Pg. 361-6 (Aug 2013) ISSN: 1791-3004 [Electronic] Greece
PMID23732925 (Publication Type: Journal Article, Retracted Publication)
Chemical References
  • CA 074 methyl ester
  • Carrier Proteins
  • Dipeptides
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Cathepsin B
Topics
  • Animals
  • Carrier Proteins (metabolism)
  • Cathepsin B (antagonists & inhibitors)
  • Dipeptides (administration & dosage, pharmacology)
  • Disease Models, Animal
  • Fibrosis
  • Interleukin-1beta (metabolism)
  • Male
  • Myocardial Infarction (drug therapy, metabolism, physiopathology)
  • Myocardium (metabolism, pathology)
  • Myocytes, Cardiac (drug effects, metabolism, pathology)
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Rats
  • Signal Transduction (drug effects)
  • Ventricular Remodeling (drug effects)

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