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

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.

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.

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.