Cathepsin B deteriorates diabetic cardiomyopathy induced by streptozotocin via promoting NLRP3-mediated pyroptosis

Cathepsin B (CTSB), a member of lysosomal cathepsin, is involved in cell autophagy and apoptosis. We previously re-ported that CTSB increased cardiomyocyte apoptosis in mice heart during pressure overload, while the role of CTSB on diabetic cardiomyopathy has not been fully elucidated. The aim of this study is to explore the role and the underlying mechanism of CTSB on diabetic cardiomyopathy. Mice were subjected to streptozotocin injection to induce a diabetes model. Neonatal rat cardiomyocytes were isolated and cultured with high glucose (33.3 mM) to establish an in vitro model. CTSB protein level was increased in diabetic cardiomyopathy (DCM) mice heart as well as in cardiomyo-cytes stimulated with high glucose. CTSB knockout mice showed ameliorated cardiac function, cardiac fibrosis, cardiac inflammation, and pyroptosis level. Oppositely, DCM mice with CTSB transgene showed exacerbated cardiac dysfunc-tion, fibrosis, inflammation, and pyroptosis. We found that CTSB could bind to NLR family pyrin domain containing 3 (NLRP3), thus increasing the activation of the NLRP3/ caspase-1 inflammasome pathway. When we used a NLRP3 knockout mice, the deteriorating effect of CTSB overexpres-sion via adeno-associated virus (AAV)9 delivery was abol-ished. Taken together, CTSB aggravates diabetic cardiomyop-athy via promoting NLRP3-mediated pyroptosis.