C-type natriuretic peptide co-ordinates cardiac structure and function

Abstract

Aims C-type natriuretic peptide (CNP) is an essential endothelium-derived signalling species that governs vascular homoeostasis; CNP is also expressed in the heart but an intrinsic role for the peptide in cardiac function is not established. Herein, we employ unique transgenic strains with cell-specific deletion of CNP to define a central (patho)physiological capacity of CNP in maintaining heart morphology and contractility. Methods and results Cardiac structure and function were explored in wild type (WT), cardiomyocyte (cmCNP−/−), endothelium (ecCNP−/−), and fibroblast (fbCNP−/−)—specific CNP knockout mice, and global natriuretic peptide receptor (NPR)-B−/−, and NPR-C−/− animals at baseline and in experimental models of myocardial infarction and heart failure (HF). Endothelium-specific deletion of CNP resulted in impaired coronary responsiveness to endothelium-dependent- and flow-mediated-dilatation; changes mirrored in NPR-C−/− mice. Ex vivo, global ischaemia resulted in larger infarcts and diminished functional recovery in cmCNP−/− and NPR-C−/−, but not ecCNP−/−, vs. WT. The cardiac phenotype of cmCNP−/−, fbCNP−/−, and NPR-C−/− (but not ecCNP−/− or NPR-B−/−) mice was more severe in pressure overload- and sympathetic hyperactivation-induced HF compared with WT; these adverse effects were rescued by pharmacological CNP administration in WT, but not NPR-C−/−, mice. At a molecular level, CNP/NPR-C signalling is impaired in human HF but attenuates activation of well-validated pro-hypertrophic and pro-fibrotic pathways. Conclusion C-type natriuretic peptide of cardiomyocyte, endothelial and fibroblast origins co-ordinates and preserves cardiac structure, function, and coronary vasoreactivity via activation of NPR-C. Targeting NPR-C may prove an innovative approach to treating HF and ischaemic cardiovascular disorders.

C-type natriuretic peptide moderates titin-based cardiomyocyte stiffness

“…Nitric oxide (NO), mainly released from endothelial cells, stimulates the cytosolic "soluble" guanylyl cyclase. Atrial and B-type natriuretic peptide (ANP, BNP), released from cardiomyocytes, stimulate their shared transmembrane guanylyl cyclase-A (GC-A) receptor; and C-type natriuretic peptide (CNP), released from different types of cells in the heart, activates its specific transmembrane GC-B receptor (12,13). In isolated rabbit cardiac muscle strips, pharmacological inhibition of NO signaling did not affect the decrease of passive tension in response to acute stretch.…”

Discovery of O-glycans on atrial natriuretic peptide (ANP) that affect both its proteolytic degradation and potency at its cognate receptor

“…2A). We further treated a pool of plasma samples with neuraminidase to remove only terminal sialic acid residues, followed by immunoprecipitation and detection using pAb proANP [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] , and this resulted in a mobility shift of the slower migrating 14 kDa band by ϳ1-2 kDa (Fig. 2B).…”

“…The natriuretic peptide (NP) 3 family comprises atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), and C-type natriuretic peptide (CNP), which are peptide hormones involved in maintaining cardiorenal homeostasis. The cardiac NPs, ANP and BNP, possess potent diuretic and natriuretic effects as well as blood pressure-lowering properties that are mediated through the natriuretic peptide receptor A (NPR-A), whereas CNP is a potent anti-fibrotic and anti-remodeling factor acting through natriuretic peptide receptor B (NPR-B) (1)(2)(3)(4)(5). All three NPs are synthesized as prohormones and subsequently proteolytically activated by the proprotein convertases corin and furin to form mature receptor-binding peptide hormones.…”

Effect of statin therapy on plasma C-type Natriuretic Peptides and Endothelin-1 in males with and without symptomatic coronary artery disease

“…While difficult to rigorously assess in humans, our findings from veno-arterial sampling across organs 26,27 , and recent findings linking higher values of plasma NTproCNP (and to a lesser extent, CNP) with vascular stress in adults without history of heart disease 5,6 , support the view that vascular endothelial proCNP does contribute to circulating levels in some settings. Furthermore, in endothelial cell-specific CNP knock out mice, plasma CNP is significantly reduced 9,28,29 . On the basis of these reports we conclude that if concentrations in tissues do indeed increase during statin therapy, any such increase is insufficient to affect plasma levels during the initiation of conventional doses of atorvastatin.…”