Efficacy of a cysteine protease inhibitor compared with enalapril in murine heart failure models

Cysteine 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. [Display omitted] •NPO-2270 is a potent and selective cysteine protease inhibitor•NPO-2270 limits myocardial infarction and prevents adverse remodeling progression•NPO-2270 ameliorates cardiac dysfunction more effectively than enalapril•Effects of NPO-2270 correlate with reduced calpain cleavage of junctophilin-2 Cardiovascular medicine; Cell biology