Journal article
Efficacy of a cysteine protease inhibitor compared with enalapril in murine heart failure models
iScience, Vol.27(10), 110935
10/18/2024
DOI: 10.1016/j.isci.2024.110935
PMCID: PMC11458958
PMID: 39381741
Abstract
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.
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•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
Details
- Title: Subtitle
- Efficacy of a cysteine protease inhibitor compared with enalapril in murine heart failure models
- Creators
- David Aluja - Hebron UniversitySara Delgado-Tomás - Hebron UniversityJose A. Barrabés - Hebron UniversityElisabet Miró-Casas - Hebron UniversityMarisol Ruiz-Meana - Hebron UniversityAntonio Rodríguez-Sinovas - Hebron UniversityBegoña Benito - Hebron UniversityJinxi Wang - University of IowaLong-Sheng Song - University of IowaIgnacio Ferreira-González - Hebron UniversityJavier Inserte - Hebron University
- Resource Type
- Journal article
- Publication Details
- iScience, Vol.27(10), 110935
- DOI
- 10.1016/j.isci.2024.110935
- PMID
- 39381741
- PMCID
- PMC11458958
- NLM abbreviation
- iScience
- ISSN
- 2589-0042
- eISSN
- 2589-0042
- Publisher
- Elsevier Inc
- Grant note
- Instituto de Salud Carlos III, Spain: PI20/01681, AES PI23/00068 CIBERCV: CB16/11/00479 Sociedad Espanolaola de Cardiologimath;a: SEC/FEC-INV-BAS 22/013 Fundaciola Maratode TV3: FLMTV3/202321-3 0-31, PERIS STL/484/2023
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 Espanolaola de Cardiolog & imath;a (SEC/FEC-INV-BAS 22/013) ; Fundaciola Maratode TV3 (FLMTV3/202321-3 0-31) and PERIS STL/484/2023. Long-Sheng Song is supported by the National Institutes of Health of USA.
- Language
- English
- Date published
- 10/18/2024
- Academic Unit
- Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Internal Medicine
- Record Identifier
- 9984704842102771
Metrics
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