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Exercise Attenuates Acute β-Adrenergic Overactivation–Induced Cardiac Fibrosis by Modulating Cytokines

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Abstract

During acute sympathetic stress, the overactivation of β-adrenergic receptors (β-ARs) causes cardiac fibrosis by triggering inflammation and cytokine expression. It is unknown whether exercise training inhibits acute β-AR overactivation–induced cytokine expression and cardiac injury. Here, we report that running exercise inhibited cardiac fibrosis and improved cardiac function in mice treated with isoproterenol (ISO), a β-AR agonist. A cytokine antibody array revealed that running exercise prevented most of the changes in cytokine expression induced by ISO. Specifically, ISO-induced upregulation of 18 cytokines was prevented by running exercise. A Kyoto encyclopedia of genes and genomes analysis of these cytokines revealed that Hedgehog and RAP1 signaling pathways were involved in the regulation of cytokine expression by exercise. The changes in the expression of some cytokines that were prevented by exercise were verified by an enzyme-linked immunosorbent assay and real-time PCR. In conclusion, running exercise prevented the cytokine expression changes after acute β-AR overactivation and therefore attenuated cardiac fibrosis. Acute sympathetic stress is an important risk factor for the patients with cardiovascular diseases, and the present study revealed that exercise training can prevent against the upregulation of cytokines and the subsequent cardiac injury induced by acute sympathetic stress, suggesting that exercise training may be beneficial for cardiovascular patients who are in risk of acute sympathetic stress. This finding provides a theoretical basis for the application of exercise training in patients who may suffer from acute sympathetic stress.

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Abbreviations

ELISA:

Enzyme-linked immunosorbent assay

GO:

Gene ontology

IL-1RN:

Interleukin-1 receptor antagonist

ISO:

Isoproterenol

KEGG:

Kyoto encyclopedia of genes and genomes

MMP2:

Matrix metalloprotein 2

MOK:

MAPK/MAK/MRK overlapping kinase

PCA:

Principal component analysis

RAP1:

Ras-related protein 1

Sed:

Sedentary

SPP1:

Osteopontin

TNFRSF1B:

Tumor necrosis factor receptor superfamily member 1B

β-AR:

β-Adrenergic receptor

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Funding

This work was supported by the Beijing Natural Science Foundation (grant No. 7182176 to Wei Gao), the National Natural Science Foundation of China (grant No. 81670205 to Han Xiao, grant No. 81530009 to Youyi Zhang, and grant No. 81871850 to Haiyi Yu), the Open Foundation from Beijing Key Laboratory of Hypertension Research (grant No. 2017GXY-KFKT-05), and the Fund for Fostering Young Scholars of Peking University Health Science Center (grant No. BMU2017PY016).

Author information

Author notes

  1. Akehu Alemasi and Ning Cao contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital; NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education; Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University Third Hospital, Beijing, 100191, China

    Akehu Alemasi, Ning Cao, Xiangbo An, Jimin Wu, Huijun Gu, Haiyi Yu, Yao Song, Youyi Zhang, Han Xiao & Wei Gao

  2. Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China

    Huijun Gu

  3. Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China

    Huan Wang

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  1. Akehu Alemasi
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  11. Wei Gao
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Corresponding authors

Correspondence to Han Xiao or Wei Gao.

Ethics declarations

The animal experiment was approved by the Committee of Peking University on Ethics of Animal Experiments (Approval number: LA 2010–036). The procedures were conducted according to the US National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publication No. 85-23, revised 1996) and the Guidelines for Animal Experiments, Peking University Health Science Center.

Human Subjects/Informed Consent Statement

No experiments on human subjects were carried out.

Ethical Approval of Animal Studies

All institutional and national guidelines for the care and use of laboratory animals were followed and approved by the appropriate institutional committees.

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The authors declare that they have no conflict of interest.

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Associate Editor Junjie Xiao oversaw the review of this article

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Alemasi, A., Cao, N., An, X. et al. Exercise Attenuates Acute β-Adrenergic Overactivation–Induced Cardiac Fibrosis by Modulating Cytokines. J. of Cardiovasc. Trans. Res. 12, 528–538 (2019). https://doi.org/10.1007/s12265-019-09894-1

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