C-type natriuretic peptide co-ordinates cardiac structure and function
<p><strong>Aims:</strong> 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...
| Auteurs principaux: | , , , |
|---|---|
| Format: | Journal article |
| Publié: |
Oxford University Press
2019
|
| _version_ | 1826304634470268928 |
|---|---|
| author | Chu, SM Moyes, AJ Aubdool, AA Hobbs, AJ |
| author_facet | Chu, SM Moyes, AJ Aubdool, AA Hobbs, AJ |
| author_sort | Chu, SM |
| collection | OXFORD |
| description | <p><strong>Aims:</strong> 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.</p> <p><strong>Methods and results:</strong> 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.</p> <p><strong>Conclusion:</strong> 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.</p> |
| first_indexed | 2024-03-07T06:20:47Z |
| format | Journal article |
| id | oxford-uuid:f2a4c27c-1058-445c-9ff7-974a78627b01 |
| institution | University of Oxford |
| last_indexed | 2024-03-07T06:20:47Z |
| publishDate | 2019 |
| publisher | Oxford University Press |
| record_format | dspace |
| spelling | oxford-uuid:f2a4c27c-1058-445c-9ff7-974a78627b012022-03-27T12:05:30ZC-type natriuretic peptide co-ordinates cardiac structure and functionJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:f2a4c27c-1058-445c-9ff7-974a78627b01Symplectic Elements at OxfordOxford University Press2019Chu, SMMoyes, AJAubdool, AAHobbs, AJ <p><strong>Aims:</strong> 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.</p> <p><strong>Methods and results:</strong> 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.</p> <p><strong>Conclusion:</strong> 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.</p> |
| spellingShingle | Chu, SM Moyes, AJ Aubdool, AA Hobbs, AJ C-type natriuretic peptide co-ordinates cardiac structure and function |
| title | C-type natriuretic peptide co-ordinates cardiac structure and function |
| title_full | C-type natriuretic peptide co-ordinates cardiac structure and function |
| title_fullStr | C-type natriuretic peptide co-ordinates cardiac structure and function |
| title_full_unstemmed | C-type natriuretic peptide co-ordinates cardiac structure and function |
| title_short | C-type natriuretic peptide co-ordinates cardiac structure and function |
| title_sort | c type natriuretic peptide co ordinates cardiac structure and function |
| work_keys_str_mv | AT chusm ctypenatriureticpeptidecoordinatescardiacstructureandfunction AT moyesaj ctypenatriureticpeptidecoordinatescardiacstructureandfunction AT aubdoolaa ctypenatriureticpeptidecoordinatescardiacstructureandfunction AT hobbsaj ctypenatriureticpeptidecoordinatescardiacstructureandfunction |