Pharmacological administration of exogenous C-type natriuretic peptide significantly reduced right ventricular systolic pressure and promoted anti-remodeling signaling in mice with pulmonary hypertension.
Does exogenous CNP administration reduce pulmonary hypertension and right ventricular remodeling in mice with established PH?
Endothelium-derived CNP protects against pulmonary hypertension, and exogenous CNP administration reduces pulmonary vascular pressure and right ventricular remodeling in a preclinical model.
In the systemic circulation, C-type natriuretic peptide (CNP) fulfils a multimodal homeostatic function, modulating many processes relevant to pulmonary hypertension (PH), including local blood flow, vascular remodeling and cardiac function. We explored a parallel, protective role for CNP in the pulmonary circulation and right ventricle, and investigated the potential for exploiting natriuretic peptide receptor (NPR) signaling in the context of PH. The development of PH was explored in wildtype (WT), endothelium-restricted (ecCNP -/- ), cardiomyocyte-specific (cmCNP -/- ) CNP knockout and global NPR-C (NPR-C -/- ) mice exposed to hypoxia (10% O 2 ) plus the vascular endothelial growth factor receptor antagonist Sugen (SuHx) for 5 weeks. To investigate the therapeutic potential of NPR signaling, exogenous CNP was administered via subcutaneous osmotic minipump to animals with established PH. The development of PH, including right ventricular systolic pressure (RVSP), right ventricular hypertrophy (RVH) and RV fibrosis, was accentuated in ecCNP -/- mice exposed to SuHx, whereas global deletion of NPR-C specifically exacerbated the development of RVH and fibrosis without altering RVSP. In contrast, loss of cardiomyocyte-derived CNP did not result in a significant adverse phenotype. Pharmacological CNP administration significantly reduced RVSP and promoted anti-proliferative, anti-remodeling signaling in the cardiopulmonary circulation. These data elucidate the protective role of endogenous CNP signaling against the development of PH and provide preliminary evidence for the therapeutic potential of targeting CNP-dependent pathways, including both cognate NPR-B and NPR-C, in the context of pulmonary vascular disease and RV remodeling. • C-type natriuretic peptide (CNP) is a critical regulator of vascular and cardiac homeostasis • Pulmonary hypertension (PH) is characterized by perturbations in CNP-regulated mechanisms • Endothelium-derived CNP protects against PH by reducing pulmonary vascular pressure and remodeling, and right ventricular (RV) hypertrophy and fibrosis • Administration of exogenous CNP can protect against PH • The beneficial actions of CNP are mediated via NPR-B and NPR-C • Pharmacological targeting of CNP represents a novel therapeutic avenue in PH
Dignam et al. (Tue,) conducted a other in Pulmonary hypertension. Exogenous C-type natriuretic peptide (CNP) was evaluated on Right ventricular systolic pressure (RVSP), right ventricular hypertrophy (RVH) and RV fibrosis. Pharmacological administration of exogenous C-type natriuretic peptide significantly reduced right ventricular systolic pressure and promoted anti-remodeling signaling in mice with pulmonary hypertension.
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