C-Type Natriuretic Peptide: A Multifaceted Paracrine Regulator in the Heart and Vasculature

Abstract

C-type natriuretic peptide (CNP) is an autocrine and paracrine mediator released by endothelial cells, cardiomyocytes and fibroblasts that regulates vital physiological functions in the cardiovascular system. These roles are conveyed via two cognate receptors, natriuretic peptide receptor B (NPR-B) and natriuretic peptide receptor C (NPR-C), which activate different signalling pathways that mediate complementary yet distinct cellular responses. Traditionally, CNP has been deemed the endothelial component of the natriuretic peptide system, while its sibling peptides, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), are considered the endocrine guardians of cardiac function and blood volume. However, accumulating evidence indicates that CNP not only modulates vascular tone and blood pressure, but also governs a wide range of cardiovascular effects including the control of inflammation, angiogenesis, smooth muscle and endothelial cell proliferation, atherosclerosis, cardiomyocyte contractility, hypertrophy, fibrosis, and cardiac electrophysiology. This review will focus on the novel physiological functions ascribed to CNP, the receptors/signalling mechanisms involved in mediating its cardioprotective effects, and the development of therapeutics targeting CNP signalling pathways in different disease pathologies.

Increasing heart vascularisation after myocardial infarction using brain natriuretic peptide stimulation of endothelial and WT1+epicardium-derived cells

“…Thus, part of the cardioprotective effect of BNP in infarcted hearts is probably due to accelerated and/or increased neovascularisation in both the ZI+BZ and RZ. This result corroborates works reporting that natriuretic peptides stimulate angiogenesis and vasculogenesis during development and in adult ischemic organs 33,34 .…”

C-type natriuretic peptide moderates titin-based cardiomyocyte stiffness

“…In addition CNP, via GC-B and possibly also NPR-C signaling, acts on other types of cells in the heart, such as fibroblasts, immune cells, and vascular cells (12,13,(18)(19)(20)(21)34). Thereby CNP may not only moderate cardiomyocyte stiffness and dysfunction (present studies) but also improve coronary perfusion and attenuate the hypertrophic, fibrotic, and inflammatory responses of the heart to ischemia and hypertension (12,13,42).…”

Pulmonary Arterial Hypertension Due to NPR-C Mutation: A Novel Paradigm for Normal and Pathologic Remodeling?

“…Various studies have demonstrated that NPR-C can inhibit the AC/cAMP signal transduction and elicit physiological functions [22]. Natriuretic peptides such as ANP, CNP and BNP have been reported to inhibit AC and decrease cAMP levels in a variety of tissues and cells by interacting with NPR-C receptor [22,23]. In addition, activation of NPR-C signaling may decrease L-type calcium current in single sinuatrial node cells by AC inhibition and decreased cAMP levels [24].…”