NPRC deletion attenuates cardiac fibrosis in diabetic mice by activating PKA/PKG and inhibiting TGF-β1/Smad pathways

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Abstract

Cardiac fibrosis plays a key role in the progression of diabetic cardiomyopathy (DCM). Previous studies demonstrated the cardioprotective effects of natriuretic peptides. However, the effects of natriuretic peptide receptor C (NPRC) on cardiac fibrosis in DCM remains unknown. Here, we observed that myocardial NPRC expression was increased in mice and patients with DCM. NPRC ^−/− diabetic mice showed alleviated cardiac fibrosis, as well as improved cardiac function and remodeling. NPRC knockdown in both cardiac fibroblasts and cardiomyocytes decreased collagen synthesis and proliferation of cardiac fibroblasts. RNA sequencing identified that NPRC deletion up-regulated the expression of TGF-β–induced factor homeobox 1 (TGIF1), which inhibited the phosphorylation of Smad2/3. Furthermore, TGIF1 up-regulation was mediated by the activation of cAMP/PKA and cGMP/PKG signaling induced by NPRC deletion. These findings suggest that NPRC deletion attenuated cardiac fibrosis and improved cardiac remodeling and function in diabetic mice, providing a promising approach to the treatment of diabetic cardiac fibrosis.

Abstract

NPRC deletion attenuates cardiac fibrosis in diabetic mice by inhibiting TGF-β1/Smad pathway through the activation of PKA/PKG.

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Author and article information

Contributors

Linlin Meng:

ORCID: https://orcid.org/0009-0003-6640-3654

Role: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Yue Lu: Role: InvestigationRole: MethodologyRole: ValidationRole: Writing - review & editing

Xinlu Wang: Role: Data curationRole: MethodologyRole: ValidationRole: Visualization

Cheng Cheng: Role: Data curationRole: InvestigationRole: Methodology

Fei Xue:

ORCID: https://orcid.org/0000-0001-7047-8497

Role: Formal analysisRole: ValidationRole: Writing - review & editing

Lin Xie: Role: InvestigationRole: ValidationRole: Visualization

Yaoyuan Zhang: Role: Data curationRole: ValidationRole: Writing - review & editing

Wenhai Sui:

ORCID: https://orcid.org/0000-0001-6114-0443

Role: Funding acquisitionRole: MethodologyRole: ResourcesRole: Writing - original draftRole: Writing - review & editing

Meng Zhang:

ORCID: https://orcid.org/0000-0002-3307-1820

Role: ConceptualizationRole: Funding acquisitionRole: Validation

Yun Zhang:

ORCID: https://orcid.org/0000-0003-4432-6144

Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: Writing - original draftRole: Writing - review & editing

Cheng Zhang:

ORCID: https://orcid.org/0000-0003-3672-6543

Role: ConceptualizationRole: Funding acquisitionRole: Project administrationRole: ResourcesRole: SupervisionRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Journal

Journal ID (nlm-ta): Sci Adv

Journal ID (iso-abbrev): Sci Adv

Journal ID (publisher-id): sciadv

Journal ID (hwp): advances

Title: Science Advances

Publisher: American Association for the Advancement of Science

ISSN (Electronic): 2375-2548

Publication date Collection: August 2023

Publication date (Electronic, pub): 02 August 2023

Volume: 9

Issue: 31

Electronic Location Identifier: eadd4222

Affiliations

[1]National Key Laboratory for Innovation and Transformation of Luobing Theory; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences; Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China.

Author notes

[* ]Corresponding author. Email: zhangyun@ 123456sdu.edu.cn (Y.Z.); zhangc@ 123456sdu.edu.cn (C.Z.)

Author information

Linlin Meng https://orcid.org/0009-0003-6640-3654

Fei Xue https://orcid.org/0000-0001-7047-8497

Wenhai Sui https://orcid.org/0000-0001-6114-0443

Meng Zhang https://orcid.org/0000-0002-3307-1820

Yun Zhang https://orcid.org/0000-0003-4432-6144

Cheng Zhang https://orcid.org/0000-0003-3672-6543

Article

Publisher ID: add4222

DOI: 10.1126/sciadv.add4222

PMC ID: 10396312

PubMed ID: 37531438

SO-VID: 25c02fc4-4cf9-4f29-af02-b725abbc20ed

Copyright © Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.