Departments of Medicine (S.P.C., D.B., N.A.-A., P.A.), Johns Hopkins School of Medicine, Baltimore, MD.
St. George's University of London, UK (A.A., C.B.-B.).
Circulation. 2019 Oct 29;140(18):1491-1505. doi: 10.1161/CIRCULATIONAHA.119.040676. Epub 2019 Sep 19.
Inflammation is a prominent feature of arrhythmogenic cardiomyopathy (ACM), but whether it contributes to the disease phenotype is not known.
To define the role of inflammation in the pathogenesis of ACM, we characterized nuclear factor-κB signaling in ACM models in vitro and in vivo and in cardiac myocytes from patient induced pluripotent stem cells.
Activation of nuclear factor-κB signaling, indicated by increased expression and nuclear accumulation of phospho-RelA/p65, occurred in both an in vitro model of ACM (expression of in neonatal rat ventricular myocytes) and a robust murine model of ACM (homozygous knock-in of mutant desmoglein-2 []) that recapitulates the cardiac manifestations seen in patients with ACM. Bay 11-7082, a small-molecule inhibitor of nuclear factor-κB signaling, prevented the development of ACM disease features in vitro (abnormal redistribution of intercalated disk proteins, myocyte apoptosis, release of inflammatory cytokines) and in vivo (myocardial necrosis and fibrosis, left ventricular contractile dysfunction, electrocardiographic abnormalities). Hearts of mice expressed markedly increased levels of inflammatory cytokines and chemotactic molecules that were attenuated by Bay 11-7082. Salutary effects of Bay 11-7082 correlated with the extent to which production of selected cytokines had been blocked. Nuclear factor-κB signaling was also activated in cardiac myocytes derived from a patient with ACM. These cells produced and secreted abundant inflammatory cytokines under basal conditions, and this was also greatly reduced by Bay 11-7082.
Inflammatory signaling is activated in ACM and drives key features of the disease. Targeting inflammatory pathways may be an effective new mechanism-based therapy for ACM.
炎症是心律失常性心肌病（ACM）的一个显著特征，但它是否导致疾病表型尚不清楚。
为了确定炎症在 ACM 发病机制中的作用，我们在体外和体内以及患者诱导多能干细胞来源的心肌细胞中对 ACM 模型中的核因子-κB 信号进行了特征描述。
核因子-κB 信号的激活，表现为磷酸化 RelA/p65 的表达增加和核内积累，发生在体外 ACM 模型（新生大鼠心室肌细胞表达）和强有力的 ACM 小鼠模型（同源敲入突变桥粒芯糖蛋白 2 [desmoglein-2]）中，该模型重现了患者 ACM 中所见的心脏表现。核因子-κB 信号的小分子抑制剂 Bay 11-7082 可防止体外（闰盘蛋白异常重分布、心肌细胞凋亡、炎症细胞因子释放）和体内（心肌坏死和纤维化、左心室收缩功能障碍、心电图异常） ACM 疾病特征的发展。表达明显增加的炎症细胞因子和趋化因子的心脏小鼠，通过 Bay 11-7082 减弱。Bay 11-7082 的有益作用与被阻断的特定细胞因子产生程度相关。ACM 患者来源的心肌细胞中也激活了核因子-κB 信号。这些细胞在基础条件下产生和分泌丰富的炎症细胞因子，Bay 11-7082 也大大减少了这种情况。
炎症信号在 ACM 中被激活，并驱动疾病的关键特征。靶向炎症途径可能是 ACM 的一种有效的新机制治疗方法。
