An IL-6/STAT3/MR/FGF21 axis mediates heart-liver cross-talk after myocardial infarction

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Abstract

The liver plays a protective role in myocardial infarction (MI). However, very little is known about the mechanisms. Here, we identify mineralocorticoid receptor (MR) as a pivotal nexus that conveys communications between the liver and the heart during MI. Hepatocyte MR deficiency and MR antagonist spironolactone both improve cardiac repair after MI through regulation on hepatic fibroblast growth factor 21 (FGF21), illustrating an MR/FGF21 axis that underlies the liver-to-heart protection against MI. In addition, an upstreaming acute interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) pathway transmits the heart-to-liver signal to suppress MR expression after MI. Hepatocyte Il6 receptor deficiency and Stat3 deficiency both aggravate cardiac injury through their regulation on the MR/FGF21 axis. Therefore, we have unveiled an IL-6/STAT3/MR/FGF21 signaling axis that mediates heart-liver cross-talk during MI. Targeting the signaling axis and the cross-talk could provide new strategies to treat MI and heart failure.

Abstract

Activation of communications between the heart and the liver protects the heart from myocardial infarction.

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Author and article information

Contributors

Jian-Yong Sun:

ORCID: https://orcid.org/0000-0002-3919-1524

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Lin-Juan Du:

ORCID: https://orcid.org/0000-0002-1884-5672

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

Xue-Rui Shi:

ORCID: https://orcid.org/0000-0001-7201-8566

Role: Formal analysisRole: InvestigationRole: ResourcesRole: Validation

Yu-Yao Zhang:

ORCID: https://orcid.org/0000-0002-8442-9693

Role: ConceptualizationRole: InvestigationRole: MethodologyRole: ResourcesRole: Validation

Yuan Liu: Role: Formal analysisRole: InvestigationRole: ResourcesRole: Validation

Yong-Li Wang:

ORCID: https://orcid.org/0000-0002-0123-9449

Role: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: SoftwareRole: VisualizationRole: Writing - review & editing

Bo-Yan Chen:

ORCID: https://orcid.org/0000-0002-7632-2263

Role: Formal analysisRole: Investigation

Ting Liu: Role: InvestigationRole: SoftwareRole: Validation

Hong Zhu:

ORCID: https://orcid.org/0000-0002-5105-475X

Role: Investigation

Yan Liu: Role: Formal analysisRole: InvestigationRole: ResourcesRole: Validation

Cheng-Chao Ruan:

ORCID: https://orcid.org/0000-0001-5229-9428

Role: ResourcesRole: VisualizationRole: Writing - review & editing

Zhenji Gan:

ORCID: https://orcid.org/0000-0001-5940-207X

Role: MethodologyRole: Resources

Hao Ying: Role: Writing - review & editing

Zhinan Yin:

ORCID: https://orcid.org/0000-0001-6524-8777

Role: InvestigationRole: MethodologyRole: ResourcesRole: ValidationRole: Visualization

Ping-Jin Gao: Role: Project administrationRole: SupervisionRole: Writing - review & editing

Xiaoxiang Yan:

ORCID: https://orcid.org/0000-0003-3046-9902

Role: ConceptualizationRole: Data curationRole: MethodologyRole: ResourcesRole: VisualizationRole: Writing - review & editing

Ruo-Gu Li:

ORCID: https://orcid.org/0000-0002-0608-524X

Role: ConceptualizationRole: Funding acquisitionRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - review & editing

Sheng-Zhong Duan:

ORCID: https://orcid.org/0000-0002-4866-3167

Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: 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: April 2023

Publication date (Electronic, pub): 05 April 2023

Volume: 9

Issue: 14

Electronic Location Identifier: eade4110

Affiliations

[ ¹ ]Laboratory of Oral Microbiota and Systemic Diseases, Shanghai Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China.

[ ² ]National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology, Shanghai 200011, China.

[ ³ ]Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China.

[ ⁴ ]Department of Medicine, Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.

[ ⁵ ]Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China.

[ ⁶ ]State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, Chemistry and Biomedicine Innovation Center (ChemBIC), Model Animal Research Center, Nanjing University Medical School, Nanjing University, Nanjing 210061, China.

[ ⁷ ]CAS Key Laboratory of Nutrition, Metabolism, and Food Safety, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai 200031, China.

[ ⁸ ]Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine Zhuhai People’s Hospital Affiliated with Jinan University, Jinan University, Zhuhai 519000, Guangdong, China.

[ ⁹ ]The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou 510632, Guangdong, China.

[ ¹⁰ ]Department of Cardiovascular Medicine, State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.

[ ¹¹ ]Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.

[ ¹² ]Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai, China.

Author notes

[†]

These authors contributed equally to this work.

[* ]Corresponding author. Email: cardexyanxx@ 123456hotmail.com (X.Y.); 13564565961@ 123456163.com (R.-G.L.); duansz2008@ 123456hotmail.com (S.-Z.D.)

Author information

Jian-Yong Sun https://orcid.org/0000-0002-3919-1524

Lin-Juan Du https://orcid.org/0000-0002-1884-5672

Xue-Rui Shi https://orcid.org/0000-0001-7201-8566

Yu-Yao Zhang https://orcid.org/0000-0002-8442-9693

Yong-Li Wang https://orcid.org/0000-0002-0123-9449

Bo-Yan Chen https://orcid.org/0000-0002-7632-2263

Hong Zhu https://orcid.org/0000-0002-5105-475X

Cheng-Chao Ruan https://orcid.org/0000-0001-5229-9428

Zhenji Gan https://orcid.org/0000-0001-5940-207X

Zhinan Yin https://orcid.org/0000-0001-6524-8777

Xiaoxiang Yan https://orcid.org/0000-0003-3046-9902

Ruo-Gu Li https://orcid.org/0000-0002-0608-524X

Sheng-Zhong Duan https://orcid.org/0000-0002-4866-3167

Article

Publisher ID: ade4110

DOI: 10.1126/sciadv.ade4110

PMC ID: 10075967

PubMed ID: 37018396

SO-VID: 1b953beb-bd85-4990-990a-a364649e5113

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 License 4.0 (CC BY).

License:

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