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ResearchIn-Press PreviewCardiology Open Access | 10.1172/jci.insight.160416

Ablation of C-type natriuretic peptide/cGMP signaling in fibroblasts exacerbates adverse cardiac remodeling in mice

Franziska Werner,1 Estefania Prentki Santos,1 Konstanze Michel,1 Hanna Schrader,1 Katharina Völker,1 Tamara Potapenko,1 Lisa Krebes,1 Marco Abesser,1 Dorothe Möllmann,2 Martin Schlattjan,2 Hannes Schmidt,3 Boris V. Skryabin,4 Katarina Špiranec Spes,1 Kai Schuh,1 Christopher P. Denton,5 Hideo A. Baba,2 and Michaela Kuhn6

1Institute of Physiology, University of Wuerzburg, Wuerzburg, Germany

2Institute of Pathology, University Hospital Essen, Essen, Germany

3Biochemistry, University of Tuebingen, Tuebingen, Germany

4Institute of Experimental Pathology, University of Munster, Münster, Germany

5Rheumatology, Centre for Rheumatology, Royal Free and University College Medical School, London, United Kingdom

6University of Wuerzburg, Wuerzburg, Germany

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1Institute of Physiology, University of Wuerzburg, Wuerzburg, Germany

2Institute of Pathology, University Hospital Essen, Essen, Germany

3Biochemistry, University of Tuebingen, Tuebingen, Germany

4Institute of Experimental Pathology, University of Munster, Münster, Germany

5Rheumatology, Centre for Rheumatology, Royal Free and University College Medical School, London, United Kingdom

6University of Wuerzburg, Wuerzburg, Germany

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1Institute of Physiology, University of Wuerzburg, Wuerzburg, Germany

2Institute of Pathology, University Hospital Essen, Essen, Germany

3Biochemistry, University of Tuebingen, Tuebingen, Germany

4Institute of Experimental Pathology, University of Munster, Münster, Germany

5Rheumatology, Centre for Rheumatology, Royal Free and University College Medical School, London, United Kingdom

6University of Wuerzburg, Wuerzburg, Germany

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1Institute of Physiology, University of Wuerzburg, Wuerzburg, Germany

2Institute of Pathology, University Hospital Essen, Essen, Germany

3Biochemistry, University of Tuebingen, Tuebingen, Germany

4Institute of Experimental Pathology, University of Munster, Münster, Germany

5Rheumatology, Centre for Rheumatology, Royal Free and University College Medical School, London, United Kingdom

6University of Wuerzburg, Wuerzburg, Germany

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1Institute of Physiology, University of Wuerzburg, Wuerzburg, Germany

2Institute of Pathology, University Hospital Essen, Essen, Germany

3Biochemistry, University of Tuebingen, Tuebingen, Germany

4Institute of Experimental Pathology, University of Munster, Münster, Germany

5Rheumatology, Centre for Rheumatology, Royal Free and University College Medical School, London, United Kingdom

6University of Wuerzburg, Wuerzburg, Germany

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1Institute of Physiology, University of Wuerzburg, Wuerzburg, Germany

2Institute of Pathology, University Hospital Essen, Essen, Germany

3Biochemistry, University of Tuebingen, Tuebingen, Germany

4Institute of Experimental Pathology, University of Munster, Münster, Germany

5Rheumatology, Centre for Rheumatology, Royal Free and University College Medical School, London, United Kingdom

6University of Wuerzburg, Wuerzburg, Germany

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1Institute of Physiology, University of Wuerzburg, Wuerzburg, Germany

2Institute of Pathology, University Hospital Essen, Essen, Germany

3Biochemistry, University of Tuebingen, Tuebingen, Germany

4Institute of Experimental Pathology, University of Munster, Münster, Germany

5Rheumatology, Centre for Rheumatology, Royal Free and University College Medical School, London, United Kingdom

6University of Wuerzburg, Wuerzburg, Germany

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1Institute of Physiology, University of Wuerzburg, Wuerzburg, Germany

2Institute of Pathology, University Hospital Essen, Essen, Germany

3Biochemistry, University of Tuebingen, Tuebingen, Germany

4Institute of Experimental Pathology, University of Munster, Münster, Germany

5Rheumatology, Centre for Rheumatology, Royal Free and University College Medical School, London, United Kingdom

6University of Wuerzburg, Wuerzburg, Germany

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1Institute of Physiology, University of Wuerzburg, Wuerzburg, Germany

2Institute of Pathology, University Hospital Essen, Essen, Germany

3Biochemistry, University of Tuebingen, Tuebingen, Germany

4Institute of Experimental Pathology, University of Munster, Münster, Germany

5Rheumatology, Centre for Rheumatology, Royal Free and University College Medical School, London, United Kingdom

6University of Wuerzburg, Wuerzburg, Germany

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1Institute of Physiology, University of Wuerzburg, Wuerzburg, Germany

2Institute of Pathology, University Hospital Essen, Essen, Germany

3Biochemistry, University of Tuebingen, Tuebingen, Germany

4Institute of Experimental Pathology, University of Munster, Münster, Germany

5Rheumatology, Centre for Rheumatology, Royal Free and University College Medical School, London, United Kingdom

6University of Wuerzburg, Wuerzburg, Germany

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1Institute of Physiology, University of Wuerzburg, Wuerzburg, Germany

2Institute of Pathology, University Hospital Essen, Essen, Germany

3Biochemistry, University of Tuebingen, Tuebingen, Germany

4Institute of Experimental Pathology, University of Munster, Münster, Germany

5Rheumatology, Centre for Rheumatology, Royal Free and University College Medical School, London, United Kingdom

6University of Wuerzburg, Wuerzburg, Germany

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1Institute of Physiology, University of Wuerzburg, Wuerzburg, Germany

2Institute of Pathology, University Hospital Essen, Essen, Germany

3Biochemistry, University of Tuebingen, Tuebingen, Germany

4Institute of Experimental Pathology, University of Munster, Münster, Germany

5Rheumatology, Centre for Rheumatology, Royal Free and University College Medical School, London, United Kingdom

6University of Wuerzburg, Wuerzburg, Germany

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1Institute of Physiology, University of Wuerzburg, Wuerzburg, Germany

2Institute of Pathology, University Hospital Essen, Essen, Germany

3Biochemistry, University of Tuebingen, Tuebingen, Germany

4Institute of Experimental Pathology, University of Munster, Münster, Germany

5Rheumatology, Centre for Rheumatology, Royal Free and University College Medical School, London, United Kingdom

6University of Wuerzburg, Wuerzburg, Germany

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1Institute of Physiology, University of Wuerzburg, Wuerzburg, Germany

2Institute of Pathology, University Hospital Essen, Essen, Germany

3Biochemistry, University of Tuebingen, Tuebingen, Germany

4Institute of Experimental Pathology, University of Munster, Münster, Germany

5Rheumatology, Centre for Rheumatology, Royal Free and University College Medical School, London, United Kingdom

6University of Wuerzburg, Wuerzburg, Germany

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1Institute of Physiology, University of Wuerzburg, Wuerzburg, Germany

2Institute of Pathology, University Hospital Essen, Essen, Germany

3Biochemistry, University of Tuebingen, Tuebingen, Germany

4Institute of Experimental Pathology, University of Munster, Münster, Germany

5Rheumatology, Centre for Rheumatology, Royal Free and University College Medical School, London, United Kingdom

6University of Wuerzburg, Wuerzburg, Germany

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1Institute of Physiology, University of Wuerzburg, Wuerzburg, Germany

2Institute of Pathology, University Hospital Essen, Essen, Germany

3Biochemistry, University of Tuebingen, Tuebingen, Germany

4Institute of Experimental Pathology, University of Munster, Münster, Germany

5Rheumatology, Centre for Rheumatology, Royal Free and University College Medical School, London, United Kingdom

6University of Wuerzburg, Wuerzburg, Germany

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1Institute of Physiology, University of Wuerzburg, Wuerzburg, Germany

2Institute of Pathology, University Hospital Essen, Essen, Germany

3Biochemistry, University of Tuebingen, Tuebingen, Germany

4Institute of Experimental Pathology, University of Munster, Münster, Germany

5Rheumatology, Centre for Rheumatology, Royal Free and University College Medical School, London, United Kingdom

6University of Wuerzburg, Wuerzburg, Germany

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Published May 25, 2023 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.160416.
Copyright © 2023, Werner et al. 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/.
Published May 25, 2023 - Version history
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Abstract

Excessive activation of cardiac fibroblasts (CFs) in response to injury provokes cardiac fibrosis, stiffness, and failure. The local mediators counter-regulating this response remain unclear. Exogenous C-type natriuretic peptide (CNP) exerted 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 AngiotensinII (AngII) and TGF-β. Fibroblast-specific GC-B-KO mice showed enhanced fibrosis in response to AngII infusions. Moreover, after two 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 collagen I, III and periostin. Notably, such responses to AngII and TAC were greater in female as compared to male KO mice. Enhanced AngII-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.

Graphical Abstract
graphical abstract
Supplemental material

View Supplemental Figure 1 and Supplemental tables 1, 2, 3 and 4

Version history
  • Version 1 (May 25, 2023): In-Press Preview
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