Activation of T Lymphocytes as a Novel Mechanism in Beta1-Adrenergic Receptor Autoantibody-Induced Cardiac Remodeling
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.
Collectively, we demonstrate that β1-AAmAb-induced cardiac remodeling via mediating T lymphocyte disorder and releasing a variety of IL-6.
KeywordsT lymphocytes Autoantibody Receptors adrenergic Beta-1 Remodeling
Autoantibodies against the second extracellular loop of β1-adrenergic receptor
β1-AA monoclonal antibody
The second extracellular loop of β1-adrenergic receptor
Chronic heart failure
- LVID (d)
Left ventricular diastolic diameter
Left ventricular mass
Left ventricular ejection fraction
Percent fractional shortening
Enzyme-linked immunosorbent assay
Immunoglobulin fractions G
We thank Dr. Yongxiang Wei who helped us in conducting the BLI assay.
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.
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 was obtained from all individual participants included in the study.
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