Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2023
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
_version_ 1785078127994601472
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
work_keys_str_mv AT wernerfranziska ablationofctypenatriureticpeptidecgmpsignalinginfibroblastsexacerbatesadversecardiacremodelinginmice
AT prentkisantosestefania ablationofctypenatriureticpeptidecgmpsignalinginfibroblastsexacerbatesadversecardiacremodelinginmice
AT michelkonstanze ablationofctypenatriureticpeptidecgmpsignalinginfibroblastsexacerbatesadversecardiacremodelinginmice
AT schraderhanna ablationofctypenatriureticpeptidecgmpsignalinginfibroblastsexacerbatesadversecardiacremodelinginmice
AT volkerkatharina ablationofctypenatriureticpeptidecgmpsignalinginfibroblastsexacerbatesadversecardiacremodelinginmice
AT potapenkotamara ablationofctypenatriureticpeptidecgmpsignalinginfibroblastsexacerbatesadversecardiacremodelinginmice
AT krebeslisa ablationofctypenatriureticpeptidecgmpsignalinginfibroblastsexacerbatesadversecardiacremodelinginmice
AT abeßermarco ablationofctypenatriureticpeptidecgmpsignalinginfibroblastsexacerbatesadversecardiacremodelinginmice
AT mollmanndorothe ablationofctypenatriureticpeptidecgmpsignalinginfibroblastsexacerbatesadversecardiacremodelinginmice
AT schlattjanmartin ablationofctypenatriureticpeptidecgmpsignalinginfibroblastsexacerbatesadversecardiacremodelinginmice
AT schmidthannes ablationofctypenatriureticpeptidecgmpsignalinginfibroblastsexacerbatesadversecardiacremodelinginmice
AT skryabinborisv ablationofctypenatriureticpeptidecgmpsignalinginfibroblastsexacerbatesadversecardiacremodelinginmice
AT spiranecspeskatarina ablationofctypenatriureticpeptidecgmpsignalinginfibroblastsexacerbatesadversecardiacremodelinginmice
AT schuhkai ablationofctypenatriureticpeptidecgmpsignalinginfibroblastsexacerbatesadversecardiacremodelinginmice
AT dentonchristopherp ablationofctypenatriureticpeptidecgmpsignalinginfibroblastsexacerbatesadversecardiacremodelinginmice
AT babahideoa ablationofctypenatriureticpeptidecgmpsignalinginfibroblastsexacerbatesadversecardiacremodelinginmice
AT kuhnmichaela ablationofctypenatriureticpeptidecgmpsignalinginfibroblastsexacerbatesadversecardiacremodelinginmice