Cytoprotective Effects of CNP
CNP is a member of the natriuretic peptide family and, like its sibling peptides, exhibits multi-faceted cytoprotective effects in both animal models and human disease.cnp protein Endothelium derived CNP has been shown to inhibit vascular smooth muscle cell migration, to stabilise the extracellular matrix by increasing the expression of P-selectin and to attenuate endothelial dysfunction in conditions such as diabetes associated atherosclerosis and in the neointima following coronary artery intervention56.cnp protein Its cytoprotective actions are also observed in the brain, where systemic infusion of CNP reduces cerebral edema and improves cognitive function in mice with experimental traumatic brain injury (TBI).

The vasodilatory action of natriuretic peptides is mediated by activation of -ARs that are permeable to Ca2+ and promote opening of calcium channels of low voltage in the vascular smooth muscle membrane.cnp protein This induces a dilation of blood vessels which is dependent upon the concentration of CNP in the medium and the kinetics of its release from the endothelial cell.cnp protein

In addition to its vascular effects, CNP is a potent neurotrophic factor and induces proliferation of NG2 cells that are committed to generate oligodendrocytes in the central nervous system.cnp protein It also stimulates myelination in the rat striated muscle, and systemic administration of CNP significantly accelerates the growth of myelinating Schwann cells in the peripheral nerve of human volunteers with multiple sclerosis.

Endogenous CNP is secreted from vascular endothelial cells in response to a number of stimuli including pro-inflammatory cytokines such as tumour necrosis factor and interleukin 1, bacterial lipopolysaccharide and transforming growth factor-b36, 37, 44.cnp protein The production of the key mediators of inflammation and vascular remodelling, nitric oxide and chemokines such as heparin-induced thrombocytopenia, augments endothelial secretion of CNP46.

The vascular and neuroprotective effects of CNP are mediated through its binding to the NPR-C receptor, with which it forms a complex that triggers the activation of inwardly rectifying potassium channels (Kir channels) in the cell membrane45.cnp protein The EDHF-like activity of CNP in human penile resistance arteries is further linked to NPR-C activation, since the selective antagonist for this receptor M372049 attenuates EDHF responses in these arteries56.

Interestingly, it has been found that a polymorphism in the NPR-C 3'-UTR correlates with increased plasma levels of BNP and CNP in humans and this link may explain the association of a higher level of circulating CNP with heart failure and an increased risk of requiring angiography for cardiac catheterisation in this group63.cnp protein

In the developing human myelin sheath, CNP directly associates with the actin cytoskeleton and acts as an intracellular strut that counteracts compaction of the myelin basic protein (MBP) in a natriuretic peptide–MBP 'tug-of-war' mechanism, thereby keeping the axonal spaces open for diffusion of metabolites and cargo transport.cnp protein This provides a mechanistic rationale for the observation that the enlargement of axonal tongues filled with granular material in CNP-deficient mice can be prevented by reducing MBP levels64. This approach has been translated into clinical applications, with the development of CD-NP – a chimera of the C-terminus of Dendroaspis natriuretic peptide fused to CNP, which reproduces both the beneficial renal effects of BNP and the vasodilatory effects of CNP without the excessive hypotensive effect of the synthetic natriuretic peptides Carperitide and Nesiritide in patients with heart failure65.