Department of Cardiology, University of Heidelberg, Heidelberg, Germany.
Department of Cardiology, University of Heidelberg, Heidelberg, Germany.
Cytokine. 2019 Apr;116:139-149. doi: 10.1016/j.cyto.2018.12.022. Epub 2019 Feb 1.
Adiponectin is a hormone that together with its receptors modulates a number of metabolic processes including gluconeogenesis and lipid catabolism. It belongs to the C1QTNF (complement C1q tumor necrosis factor-related protein) family, which has a variety of members with high amino acid sequence homology and overlapping functions. Concentration of adiponectin in blood is inversely correlated with body fat percentage and cardiac risk factors like blood pressure and CRP (C-reactive protein) level. Studies have identified the existence of a cardiac adiponectin system. However, little is known about the role of this system in the pathogenesis of autoimmune myocarditis. Thus, we have studied the involvement of adiponectin in the development of this autoimmune disorder in a mouse model of experimental autoimmune myocarditis (EAM).
Adiponectin knockout (ko) and wild type (wt) mice were immunized with cardiac troponin I (cTnI) to induce an EAM. To determine the severity of myocardial damage, inflammation and fibrosis were scored after HE and Afog staining and high sensitivity troponin T (hsTnT) level was measured. To detect if changes in specific inflammatory cell numbers could be observed between the genotypes, we performed immunohistochemical staining to detect T lymphocytes, B lymphocytes and macrophages. The level of the humoral immune response was determined through the measurement of cTnI-specific serum IgG autoantibodies. Relative mRNA expression of different cytokines, C1QTNF family members and adiponectin receptors in the heart tissue was analyzed with qPCR.
Animals immunized with cTnI developed autoimmune myocarditis with a significant deterioration of cardiac parameters compared to the corresponding control group. The adiponectin ko group immunized with cTnI showed a tendency towards increased inflammation, fibrosis, heart-to-body-weight ratio, infiltration pattern of T lymphocytes, B lymphocytes and macrophages, hsTnT concentration, humoral immune response and mRNA expression of interleukin 6 in the heart tissue and decreased weight gain compared to the wt group immunized with cTnI. However, the difference to the wt group treated with cTnI was not significant. The analysis of cardiac mRNA expression of adiponectin receptors and four C1QTNF family members, most suitable for fulfilling the functions of adiponectin in adiponectin ko mice, did not show any significant differences between adiponectin ko and wt group at all.
Our study reveals that the absence of adiponectin did not lead to a significantly increased impairment of cardiac function and was also unlikely to be compensated by its receptors or other C1QTNF family members in the murine model of EAM. Here, other synergistic or redundant effects might play a role and must be investigated in further studies to understand the role and function of adiponectin in autoimmune myocarditis.
脂联素是一种激素，与受体一起调节包括糖异生和脂质分解代谢在内的多种代谢过程。它属于 C1QTNF（补体 C1q 肿瘤坏死因子相关蛋白）家族，该家族具有多种具有高度氨基酸序列同源性和重叠功能的成员。血液中脂联素的浓度与体脂百分比以及血压和 CRP（C 反应蛋白）水平等心脏危险因素呈负相关。研究已经确定了心脏脂联素系统的存在。然而，对于该系统在自身免疫性心肌炎发病机制中的作用知之甚少。因此，我们在实验性自身免疫性心肌炎（EAM）的小鼠模型中研究了脂联素在这种自身免疫性疾病发展中的作用。
用心肌肌钙蛋白 I（cTnI）免疫脂联素敲除（ko）和野生型（wt）小鼠以诱导 EAM。通过 HE 和 Afog 染色评分来确定心肌损伤、炎症和纤维化的严重程度，并测量高敏肌钙蛋白 T（hsTnT）水平。为了观察基因型之间是否可以观察到特定炎性细胞数量的变化，我们进行了免疫组织化学染色以检测 T 淋巴细胞、B 淋巴细胞和巨噬细胞。通过测量 cTnI 特异性血清 IgG 自身抗体来确定体液免疫反应的水平。通过 qPCR 分析心脏组织中不同细胞因子、C1QTNF 家族成员和脂联素受体的相对 mRNA 表达。
用 cTnI 免疫的动物发生自身免疫性心肌炎，与相应的对照组相比，心脏参数明显恶化。用 cTnI 免疫的脂联素 ko 组显示出炎症、纤维化、心脏重量与体重比、T 淋巴细胞、B 淋巴细胞和巨噬细胞浸润模式、hsTnT 浓度、体液免疫反应和心脏组织中白细胞介素 6 的 mRNA 表达增加的趋势，与用 cTnI 免疫的 wt 组相比，体重增加减少。然而，与用 cTnI 处理的 wt 组相比，差异并不显著。对心脏脂联素受体和四个 C1QTNF 家族成员的 mRNA 表达进行分析，这些成员最适合在脂联素 ko 小鼠中发挥脂联素的功能，但在脂联素 ko 和 wt 组之间根本没有显示出任何显著差异。
我们的研究表明，脂联素缺失并没有导致心脏功能明显受损，在 EAM 的小鼠模型中也不太可能被其受体或其他 C1QTNF 家族成员代偿。在这里，其他协同或冗余的作用可能起作用，必须在进一步的研究中进行调查，以了解脂联素在自身免疫性心肌炎中的作用和功能。
