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Ablation of C-type natriuretic peptide/cGMP signaling in fibroblasts exacerbates adverse cardiac remodeling in mice
Excessive activation of cardiac fibroblasts (CFs) in response to injury provokes cardiac fibrosis, stiffness, and failure. The local mediators counterregulating this response remain unclear. Exogenous C-type natriuretic peptide (CNP) exerts antifibrotic effects in preclinical models. To unravel the...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10371345/ https://www.ncbi.nlm.nih.gov/pubmed/37227779 http://dx.doi.org/10.1172/jci.insight.160416 |
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author | Werner, Franziska Prentki Santos, Estefania Michel, Konstanze Schrader, Hanna Völker, Katharina Potapenko, Tamara Krebes, Lisa Abeßer, Marco Möllmann, Dorothe Schlattjan, Martin Schmidt, Hannes Skryabin, Boris V. Špiranec Spes, Katarina Schuh, Kai Denton, Christopher P. Baba, Hideo A. Kuhn, Michaela |
author_facet | Werner, Franziska Prentki Santos, Estefania Michel, Konstanze Schrader, Hanna Völker, Katharina Potapenko, Tamara Krebes, Lisa Abeßer, Marco Möllmann, Dorothe Schlattjan, Martin Schmidt, Hannes Skryabin, Boris V. Špiranec Spes, Katarina Schuh, Kai Denton, Christopher P. Baba, Hideo A. Kuhn, Michaela |
author_sort | Werner, Franziska |
collection | PubMed |
description | Excessive activation of cardiac fibroblasts (CFs) in response to injury provokes cardiac fibrosis, stiffness, and failure. The local mediators counterregulating this response remain unclear. Exogenous C-type natriuretic peptide (CNP) exerts antifibrotic effects in preclinical models. To unravel the role of the endogenous hormone, we generated mice with fibroblast-restricted deletion (KO) of guanylyl cyclase-B (GC-B), the cGMP-synthesizing CNP receptor. CNP activated GC-B/cGMP signaling in human and murine CFs, preventing proliferative and promigratory effects of angiotensin II (Ang II) and TGF-β. Fibroblast-specific GC-B–KO mice showed enhanced fibrosis in response to Ang II infusions. Moreover, after 2 weeks of mild pressure overload induced by transverse aortic constriction (TAC), such KO mice had augmented cardiac fibrosis and hypertrophy, together with systolic and diastolic contractile dysfunction. This was associated with increased expression of the profibrotic genes encoding collagen I, III, and periostin. Notably, such responses to Ang II and TAC were greater in female as compared with male KO mice. Enhanced Ang II–induced CNP expression in female hearts and augmented GC-B expression and activity in female CFs may contribute to this sex disparity. The results show that paracrine CNP signaling in CFs has antifibrotic and antihypertrophic effects. The CNP/GC-B/cGMP pathway might be a target for therapies combating pathological cardiac remodeling. |
format | Online Article Text |
id | pubmed-10371345 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
spelling | pubmed-103713452023-07-27 Ablation of C-type natriuretic peptide/cGMP signaling in fibroblasts exacerbates adverse cardiac remodeling in mice Werner, Franziska Prentki Santos, Estefania Michel, Konstanze Schrader, Hanna Völker, Katharina Potapenko, Tamara Krebes, Lisa Abeßer, Marco Möllmann, Dorothe Schlattjan, Martin Schmidt, Hannes Skryabin, Boris V. Špiranec Spes, Katarina Schuh, Kai Denton, Christopher P. Baba, Hideo A. Kuhn, Michaela JCI Insight Research Article Excessive activation of cardiac fibroblasts (CFs) in response to injury provokes cardiac fibrosis, stiffness, and failure. The local mediators counterregulating this response remain unclear. Exogenous C-type natriuretic peptide (CNP) exerts antifibrotic effects in preclinical models. To unravel the role of the endogenous hormone, we generated mice with fibroblast-restricted deletion (KO) of guanylyl cyclase-B (GC-B), the cGMP-synthesizing CNP receptor. CNP activated GC-B/cGMP signaling in human and murine CFs, preventing proliferative and promigratory effects of angiotensin II (Ang II) and TGF-β. Fibroblast-specific GC-B–KO mice showed enhanced fibrosis in response to Ang II infusions. Moreover, after 2 weeks of mild pressure overload induced by transverse aortic constriction (TAC), such KO mice had augmented cardiac fibrosis and hypertrophy, together with systolic and diastolic contractile dysfunction. This was associated with increased expression of the profibrotic genes encoding collagen I, III, and periostin. Notably, such responses to Ang II and TAC were greater in female as compared with male KO mice. Enhanced Ang II–induced CNP expression in female hearts and augmented GC-B expression and activity in female CFs may contribute to this sex disparity. The results show that paracrine CNP signaling in CFs has antifibrotic and antihypertrophic effects. The CNP/GC-B/cGMP pathway might be a target for therapies combating pathological cardiac remodeling. American Society for Clinical Investigation 2023-07-10 /pmc/articles/PMC10371345/ /pubmed/37227779 http://dx.doi.org/10.1172/jci.insight.160416 Text en © 2023 Werner et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Werner, Franziska Prentki Santos, Estefania Michel, Konstanze Schrader, Hanna Völker, Katharina Potapenko, Tamara Krebes, Lisa Abeßer, Marco Möllmann, Dorothe Schlattjan, Martin Schmidt, Hannes Skryabin, Boris V. Špiranec Spes, Katarina Schuh, Kai Denton, Christopher P. Baba, Hideo A. Kuhn, Michaela Ablation of C-type natriuretic peptide/cGMP signaling in fibroblasts exacerbates adverse cardiac remodeling in mice |
title | Ablation of C-type natriuretic peptide/cGMP signaling in fibroblasts exacerbates adverse cardiac remodeling in mice |
title_full | Ablation of C-type natriuretic peptide/cGMP signaling in fibroblasts exacerbates adverse cardiac remodeling in mice |
title_fullStr | Ablation of C-type natriuretic peptide/cGMP signaling in fibroblasts exacerbates adverse cardiac remodeling in mice |
title_full_unstemmed | Ablation of C-type natriuretic peptide/cGMP signaling in fibroblasts exacerbates adverse cardiac remodeling in mice |
title_short | Ablation of C-type natriuretic peptide/cGMP signaling in fibroblasts exacerbates adverse cardiac remodeling in mice |
title_sort | ablation of c-type natriuretic peptide/cgmp signaling in fibroblasts exacerbates adverse cardiac remodeling in mice |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10371345/ https://www.ncbi.nlm.nih.gov/pubmed/37227779 http://dx.doi.org/10.1172/jci.insight.160416 |
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