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

• Published in: Pharmacological research Vol. 209; p. 107447
• Main Authors: Lowe, Vanessa J., Aubdool, Aisah A., Moyes, Amie J., Dignam, Joshua P., Perez-Ternero, C., Baliga, Reshma S., Smart, Nicola, Hobbs, Adrian J.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01-11-2024
• Subjects: Angiogenesis; C-type natriuretic peptide; Fibrosis; Myocardial infarction; Natriuretic peptide receptor-C; Myocardial infarction; Angiogenesis; C-type natriuretic peptide; Natriuretic peptide receptor-C; Fibrosis
• ISSN: 1043-6618; 1096-1186; 1096-1186
• DOI: 10.1016/j.phrs.2024.107447

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.
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.
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.
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.
•Myocardial infarction (MI) is characterised by perturbations in mechanisms regulated by C-type natriuretic peptide (CNP)•Cardiomyocyte-derived CNP protects against myocardial ischaemia by promoting neovascularisation and reducing fibrotic burden•Pharmacological administration of CNP also protects against myocardial ischaemia•The beneficial actions of CNP are mediated via cognate natriuretic peptide receptor (NPR)-C•Pharmacological targeting of CNP and/or NPR-C signalling represents a novel therapeutic avenue in MI