Beijing Anzhen Hospital, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Capital Medical University, Beijing, 100029, China.
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
Cardiovasc Drugs Ther. 2019 Apr;33(2):149-161. doi: 10.1007/s10557-019-06856-2.
Numerous studies have reported significantly elevated titers of serum autoantibody against the second extracellular loop of β-adrenoceptor (β-AA), a catecholamine-like substance with β-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-AA remains unclear. The current study was designed to determine whether T cell disorder contributes to heart failure induced by β-AA.
β-AA monoclonal antibodies (β-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-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-AAmAb treatment. Mechanistic studies in vitro demonstrated that T lymphocyte culture supernatants stimulated by β-AAmAb caused direct damage in the cardiomyocytes, and β-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-AAmAb-induced cardiac remodeling.
Collectively, we demonstrate that β-AAmAb-induced cardiac remodeling via mediating T lymphocyte disorder and releasing a variety of IL-6.
许多研究报告称，心力衰竭患者血清中对β-肾上腺素能受体（β-AA）第二细胞外环的自身抗体滴度显著升高，β-AA 是一种具有β-肾上腺素能活性的儿茶酚胺样物质。尽管有证据表明，这种自身抗体可能改变 T 细胞的增殖和分泌，但β-AA 引起心力衰竭的 T 淋巴细胞的作用尚不清楚。本研究旨在确定 T 细胞紊乱是否导致β-AA 诱导的心力衰竭。
使用杂交瘤技术产生的β-AA 单克隆抗体（β-AAmAb）在野生型小鼠或 T 淋巴细胞缺陷裸鼠中给予 12 周。体外使用心力衰竭患者的 T 淋巴细胞和新生心肌细胞。采用小鼠蛋白抗体阵列分析检测导致β-AAmAb 诱导心力衰竭的细胞因子。与野生型小鼠相比，T 淋巴细胞缺陷小鼠阻止了心脏功能的恶化，减轻了不良重构，并改善了心肌细胞凋亡和纤维化。蛋白阵列显示，与野生型小鼠相比，β-AAmAb 处理后裸鼠血清中白细胞介素（IL）-6 水平显著降低。体外机制研究表明，β-AAmAb 刺激的 T 淋巴细胞培养上清液直接损伤心肌细胞，β-AAmAb 促进分离自心力衰竭患者的 T 淋巴细胞增殖，并增加 IL-6 释放。IL-6 特异性 siRNA 几乎完全消除了心肌细胞凋亡，提示 IL-6 可能是 T 淋巴细胞释放的关键细胞因子，负责β-AAmAb 诱导的心脏重构。
综上所述，我们证明β-AAmAb 通过介导 T 淋巴细胞紊乱和释放多种 IL-6 诱导心脏重构。
