Cardiomyocyte-derived C-type natriuretic peptide diminishes myocardial ischaemic injury by promoting revascularisation and limiting fibrotic burden.

Autor: Lowe VJ; William Harvey Research Institute, Faculty of Medicine & Dentistry, Barts & The London, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK., Aubdool AA; William Harvey Research Institute, Faculty of Medicine & Dentistry, Barts & The London, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK., Moyes AJ; William Harvey Research Institute, Faculty of Medicine & Dentistry, Barts & The London, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK., Dignam JP; William Harvey Research Institute, Faculty of Medicine & Dentistry, Barts & The London, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK., Perez-Ternero C; William Harvey Research Institute, Faculty of Medicine & Dentistry, Barts & The London, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK., Baliga RS; William Harvey Research Institute, Faculty of Medicine & Dentistry, Barts & The London, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK., Smart N; Institute of Developmental and Regenerative Medicine, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX3 7TY, UK., Hobbs AJ; William Harvey Research Institute, Faculty of Medicine & Dentistry, Barts & The London, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. Electronic address: a.j.hobbs@qmul.ac.uk.
Jazyk: angličtina
Zdroj: Pharmacological research [Pharmacol Res] 2024 Nov; Vol. 209, pp. 107447. Date of Electronic Publication: 2024 Oct 05.
DOI: 10.1016/j.phrs.2024.107447
Abstrakt: Background: C-type natriuretic peptide (CNP) is a significant player in the maintenance of cardiac and vascular homeostasis regulating local blood flow, platelet and leukocyte activation, heart structure and function, angiogenesis and metabolic balance. Since such processes are perturbed in myocardial infarction (MI), we explored the role of cardiomyocyte-derived CNP, and pharmacological administration of the peptide, in offsetting the pathological consequences of MI.
Methods: Wild type (WT) and cardiomyocyte-restricted CNP null (cmCNP -/- ) mice were subjected to left anterior descending coronary artery (LADCA) ligation and acute effects on infarct size and longer-term outcomes of cardiac repair explored. Heart structure and function were assessed by combined echocardiographic and molecular analyses. Pharmacological administration of CNP (0.2 mg/kg/day; s.c.) was utilized to assess therapeutic potential.
Results: Compared to WT littermates, cmCNP -/- mice had a modestly increased infarct size following LADCA ligation but without significant deterioration of cardiac structural and functional indices. However, cmCNP -/- animals exhibited overtly worse heart morphology and contractility 6 weeks following MI, with particularly deleterious reductions in left ventricular ejection fraction, dilatation, fibrosis and revascularization. This phenotype was largely recapitulated in animals with global deletion of natriuretic peptide receptor (NPR)-C (NPR-C -/- ). Pharmacological administration of CNP rescued the deleterious pathology in WT and cmCNP -/- , but not NPR-C -/- , animals.
Conclusions and Implications: Cardiomyocytes synthesize and release CNP as an intrinsic protective mechanism in response to MI that reduces cardiac structural and functional deficits; these salutary actions are primarily NPR-C-dependent. Pharmacological targeting of CNP may represent a new therapeutic option for MI.
Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Adrian Hobbs reports financial support was provided by British Heart Foundation. Adrian Hobbs reports a relationship with Palatin Technologies Inc that includes: consulting or advisory. Adrian Hobbs reports a relationship with PharmaIN Corporation that includes: consulting or advisory. Adrian Hobbs reports a relationship with Novo Nordisk that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
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