Yang Yuli, Wang Qian, Cai Xingxing, Wei Zhixing, Hou Jianwen, Fei Yudong, Li Wei, Li Yigang
Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
Department of Cardiology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Aging (Albany NY). 2021 Jul 1;13(13):17473-17488. doi: 10.18632/aging.203236.
Inflammation process is an important determinant for subsequent changes in cardiac function and remodeling after acute myocardial infarction (MI). Recent studies have implicated that ALK4 haplodeficiency improves cardiac function after MI. However, it remains unknown if the beneficial effects are partly attributed to ALK4 haplodeficiency-induced modulation on inflammatory response in the inflammatory phase of MI. In this research, we aimed to explore the mechanism of ALK4 haplodeficiency in the inflammatory stage of MI.
ALK4, CD16, and CD14 were detected in peripheral blood mononuclear cells (PBMCs) isolated from MI patients and healthy volunteers. ALK4 haplodeficiency (ALK4) mice and wild-type (WT) littermates were randomly divided into the sham group and the MI group. Inflammation cytokines and chemokines were measured. Echocardiography and intracardiac electrophysiological recordings were performed on the 3 day and the 7 day after MI operation. ALK4 expression and inflammation cytokines were also detected in LPS- or IL-4-stimulated bone marrow-derived macrophages (BMDM) from the ALK4 mice and WT littermates.
ALK4 gene expression in circulating monocytes of MI patients was higher than that in those of healthy volunteers. Cardiac inflammation and vulnerability of ventricular arrhythmia after acute myocardial injury are significantly alleviated in ALK4 mice as compared to WT littermates. On the 3 day post-MI, the level of M1 macrophages were decreased in ALK4 mice as compared to WT littermates, while the level of M2 macrophages were increased on the 7 day post-MI. BMDM isolated from ALK4 mice displayed reduced secretion of pro-inflammation cytokines after stimulation by LPS in hypoxic condition and increased secretion of anti-inflammation cytokines after stimulation by IL-4. As a result, the haplodeficiency of ALK4 might be responsible for reduced inflammation response in the post-MI stage.
ALK4 haplodeficiency reduces cardiac inflammation, improves cardiac function, and finally reduces the vulnerability of ventricular arrhythmia in the inflammatory stage after MI.
炎症过程是急性心肌梗死（MI）后心脏功能及重塑后续变化的重要决定因素。近期研究表明，ALK4单倍体不足可改善MI后的心脏功能。然而，其有益作用是否部分归因于ALK4单倍体不足对MI炎症期炎症反应的调节仍不清楚。在本研究中，我们旨在探究ALK4单倍体不足在MI炎症阶段的机制。
检测从MI患者和健康志愿者分离的外周血单核细胞（PBMC）中ALK4、CD16和CD14的表达。将ALK4单倍体不足（ALK4）小鼠和野生型（WT）同窝小鼠随机分为假手术组和MI组。检测炎症细胞因子和趋化因子。在MI手术后第3天和第7天进行超声心动图和心内电生理记录。还检测了来自ALK4小鼠和WT同窝小鼠的脂多糖（LPS）或白细胞介素-4（IL-4）刺激的骨髓来源巨噬细胞（BMDM）中的ALK4表达和炎症细胞因子。
MI患者循环单核细胞中ALK4基因表达高于健康志愿者。与WT同窝小鼠相比，ALK4小鼠急性心肌损伤后的心脏炎症和室性心律失常易感性显著减轻。MI后第3天，与WT同窝小鼠相比，ALK4小鼠中M1巨噬细胞水平降低，而MI后第7天M2巨噬细胞水平升高。从ALK4小鼠分离的BMDM在缺氧条件下受LPS刺激后促炎细胞因子分泌减少，受IL-4刺激后抗炎细胞因子分泌增加。因此，ALK4单倍体不足可能是MI后阶段炎症反应减轻的原因。
ALK4单倍体不足可减轻心脏炎症，改善心脏功能，并最终降低MI后炎症阶段室性心律失常的易感性。
