Cardiovascular medicine; Cell biologyMedicina cardiovascular; Biologia cel·lularMedicina cardiovascular; Biología celularCysteine proteases calpains contribute to heart failure (HF), but it remains unknown whether their inhibition provides any benefit compared to standard pharmacological treatment for HF. Here, we characterize the pharmacological properties of NPO-2270 (NPO) as a potent inhibitor of cysteine proteases. Then, we describe that acute administration of NPO in rodent models of transient ischemia at the time of reperfusion reduces myocardial infarction, while its chronic oral administration attenuates adverse remodeling and cardiac dysfunction induced by ischemic and non-ischemic pathological stimuli more effectively than enalapril when given at the same dose. Finally, we provide evidence showing that the effects of NPO correlate with calpain inhibition and the preservation of the T-tubule morphology, due at least in part to reduced cleavage of the calpain substrate junctophilin-2. Together, our data highlight the potential of cysteine protease inhibition with NPO as a therapeutic strategy for the treatment of heart failure.This work was funded by Instituto de Salud Carlos III, Spain, through the projects AES PI20/01681 and AES PI23/00068; and the research network CIBERCV (CB16/11/00479), both cofunded by European Regional Development Fund; Sociedad Española de Cardiología (SEC/FEC-INV-BAS 22/013); Fundació la Marató de TV3 (FLMTV3/202321-30-31) and PERIS STL/484/2023. Long-Sheng Song is supported by the National Institutes of Health of USA
