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

Journal article
Authors Y. Du
X. Li
H. Yu
L. Yan
W. B. Lau
S. Zhang
Y. Qin
W. Wang
X. Ma
H. Liu
Michael Fu
Published in Cardiovascular Drugs and Therapy
Volume 33
Issue 2
Pages 149-161
ISSN 0920-3206
Publication year 2019
Published at Institute of Medicine, Department of Molecular and Clinical Medicine
Pages 149-161
Language en
Links dx.doi.org/10.1007/s10557-019-06856...
Keywords Autoantibody, Beta-1, Receptors adrenergic, Remodeling, T lymphocytes
Subject categories Cardiac and Cardiovascular Systems

Abstract

Background: Numerous studies have reported significantly elevated titers of serum autoantibody against the second extracellular loop of β 1 -adrenoceptor (β 1 -AA), a catecholamine-like substance with β 1 -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 β 1 -AA remains unclear. The current study was designed to determine whether T cell disorder contributes to heart failure induced by β 1 -AA. Methods and Results: β 1 -AA monoclonal antibodies (β 1 -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 β 1 -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 β 1 -AAmAb treatment. Mechanistic studies in vitro demonstrated that T lymphocyte culture supernatants stimulated by β 1 -AAmAb caused direct damage in the cardiomyocytes, and β 1 -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 β 1 -AAmAb-induced cardiac remodeling. Conclusions: Collectively, we demonstrate that β 1 -AAmAb-induced cardiac remodeling via mediating T lymphocyte disorder and releasing a variety of IL-6. © 2019, Springer Science+Business Media, LLC, part of Springer Nature.

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