Yunhui Du1,2, Xiao Li3, Haicun Yu2,4, Li Yan5, Wayne Bond Lau6, Shihan Zhang2,4, Yanwen Qin1, Wen Wang2,4, Xinliang Ma4,6, Huirong Liu7,8, Michael Fu9. 1. Beijing Anzhen Hospital, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Capital Medical University, Beijing, 100029, China. 2. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China. 3. Department of Pathology, School of Basic Medical Sciences, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China. 4. Beijing Key Laboratory of Metabolic Disorders Related Cardiovascular Diseases, Ministry of Education, Capital Medical University, Beijing, 100069, China. 5. Department of pathophysiology, Institute of Basic Medical Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100005, China. 6. Department of Emergency Medicine, Thomas Jefferson University, 1025 Walnut Street, College Building, Suite 808, Philadelphia, PA, 19107, USA. 7. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China. liuhr2000@126.com. 8. Beijing Key Laboratory of Metabolic Disorders Related Cardiovascular Diseases, Ministry of Education, Capital Medical University, Beijing, 100069, China. liuhr2000@126.com. 9. Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, 416 50, Gothenburg, Sweden.
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.
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 failurepatients 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 deficiencymice 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.
Entities:
Keywords:
Autoantibody; Beta-1; Receptors adrenergic; Remodeling; T lymphocytes