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

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.