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Activation of T Lymphocytes as a Novel Mechanism in Beta1-Adrenergic Receptor Autoantibody-Induced Cardiac Remodeling

  • Yunhui Du
  • Xiao Li
  • Haicun Yu
  • Li Yan
  • Wayne Bond Lau
  • Shihan Zhang
  • Yanwen Qin
  • Wen Wang
  • Xinliang Ma
  • Huirong LiuEmail author
  • Michael Fu
ORIGINAL ARTICLE

Abstract

Background

Numerous studies have reported significantly elevated titers of serum autoantibody against the second extracellular loop of β1-adrenoceptor (β1-AA), a catecholamine-like substance with β1-adrenergic activity, in patients with heart failure. Although evidence demonstrates that this autoantibody may alter T cell proliferation and secretion, the role of T lymphocytes in heart failure induced by β1-AA remains unclear. The current study was designed to determine whether T cell disorder contributes to heart failure induced by β1-AA.

Methods and Results

β1-AA monoclonal antibodies (β1-AAmAb) produced using the hybridoma technique were administered in wild-type mice or T lymphocyte deficiency nudes for 12 weeks. T lymphocytes from heart failure patients and neonatal cardiomyocytes were utilized in vitro. Mouse protein antibody array analysis was employed to detect the cytokines responsible for β1-AAmAb-induced heart failure. Compared to wild-type mice, T lymphocyte deficiency mice prevented cardiac function from getting worse, attenuated adverse remodeling, and ameliorated cardiomyocyte apoptosis and fibrosis. As shown by protein array, the serum level of interleukin (IL)-6 was significantly lower in the nude group as compared to wild-type after β1-AAmAb treatment. Mechanistic studies in vitro demonstrated that T lymphocyte culture supernatants stimulated by β1-AAmAb caused direct damage in the cardiomyocytes, and β1-AAmAb promoted proliferation of T lymphocytes isolated from patients with heart failure and increased IL-6 release. IL-6-specific siRNA virtually abolished cardiomyocyte apoptosis, suggesting that IL-6 may be a key cytokine released by T lymphocytes and responsible for β1-AAmAb-induced cardiac remodeling.

Conclusions

Collectively, we demonstrate that β1-AAmAb-induced cardiac remodeling via mediating T lymphocyte disorder and releasing a variety of IL-6.

Keywords

T lymphocytes Autoantibody Receptors adrenergic Beta-1 Remodeling 

Abbreviations

β1-AA

Autoantibodies against the second extracellular loop of β1-adrenergic receptor

β1-AAmAb

β1-AA monoclonal antibody

β1-AR

β1-adrenergic receptor

β1-AR-ECII

The second extracellular loop of β1-adrenergic receptor

CHF

Chronic heart failure

DCM

Dilated cardiomyopathy

LVID (d)

Left ventricular diastolic diameter

Lvmass

Left ventricular mass

EF

Left ventricular ejection fraction

FS

Percent fractional shortening

ELISA

Enzyme-linked immunosorbent assay

IgG

Immunoglobulin fractions G

PBS

Phosphate-buffered saline

Notes

Acknowledgements

We thank Dr. Yongxiang Wei who helped us in conducting the BLI assay.

Funding

This study was funded by the following grants: Natural Science Foundation of China 81470540 (L. Yan) and Natural Science Foundation of Beijing 7151001 (W. Wang).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

All animal experiments were performed in accordance with the guidelines for the care and use of laboratory animals, published by the Ministry of the People’s Republic of China (issued June 3, 2004), and were approved by the Institutional Committee of Animal Care at Capital Medical University.

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The Institutional Committee for the Protection of Human Subjects of Capital Medical University approved this research protocol.

Informed Consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

10557_2019_6856_MOESM1_ESM.docx (459 kb)
ESM 1 (DOCX 458 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Yunhui Du
    • 1
    • 2
  • Xiao Li
    • 3
  • Haicun Yu
    • 2
    • 4
  • Li Yan
    • 5
  • Wayne Bond Lau
    • 6
  • Shihan Zhang
    • 2
    • 4
  • Yanwen Qin
    • 1
  • Wen Wang
    • 2
    • 4
  • Xinliang Ma
    • 4
    • 6
  • Huirong Liu
    • 2
    • 4
    Email author
  • Michael Fu
    • 7
  1. 1.Beijing Anzhen Hospital, Beijing Institute of Heart, Lung and Blood Vessel DiseasesCapital Medical UniversityBeijingChina
  2. 2.Department of Physiology and Pathophysiology, School of Basic Medical SciencesCapital Medical UniversityBeijingChina
  3. 3.Department of Pathology, School of Basic Medical SciencesShandong University of Traditional Chinese MedicineJinanChina
  4. 4.Beijing Key Laboratory of Metabolic Disorders Related Cardiovascular Diseases, Ministry of EducationCapital Medical UniversityBeijingChina
  5. 5.Department of pathophysiology, Institute of Basic Medical ScienceChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
  6. 6.Department of Emergency MedicineThomas Jefferson UniversityPhiladelphiaUSA
  7. 7.Department of Molecular and Clinical Medicine, Sahlgrenska AcademyUniversity of GothenburgGothenburgSweden

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