title: 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.
authors.affiliation: Department of Cardiology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong 250021, P.R. China.
authors.forename: Aiguo
authors.initials: A
authors.lastname: Liu
authors.forename: Xuan
authors.initials: X
authors.lastname: Gao
authors.forename: Qingbin
authors.initials: Q
authors.lastname: Zhang
authors.forename: Lianqun
authors.initials: L
authors.lastname: Cui
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002401:Cathepsin B / Q000037:antagonists & inhibitors*; D004151:Dipeptides / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D005355:Fibrosis; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: C400541:CA 074 methyl ester; D002352:Carrier Proteins; D004151:Dipeptides; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D002401:Cathepsin B