Activin receptor-like kinase 4 haplodeficiency alleviates the cardiac inflammation and pacing-induced ventricular arrhythmias after myocardial infarction.
Activin receptor-like kinase 4 haplodeficiency alleviates the cardiac inflammation and pacing-induced ventricular arrhythmias after myocardial infarction.
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激活素受体样激酶4单倍体缺陷可减轻心肌梗死后心脏炎症和起搏引起的室性心律失常
DOI：
10.18632/aging.203236
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发表时间：
2021-07-01
期刊：
影响因子：
--
通讯作者：
Li Y
中科院分区：
文献类型：
--
作者：
Yang Y;Wang Q;Cai X;Wei Z;Hou J;Fei Y;Li W;Li Y
背景资料：炎症过程是急性心肌梗死（MI）后心脏功能和重塑的重要决定因素。最近的研究表明，ALK 4单倍缺陷改善MI后的心脏功能。然而，仍然不清楚有益作用是否部分归因于ALK 4单倍缺陷诱导的对MI炎症期炎症反应的调节。本研究旨在探讨ALK 4单倍缺陷在心肌梗死炎症阶段的作用机制。方法：检测MI患者和健康志愿者外周血单个核细胞（PBMCs）中ALK 4、CD 16和CD 14的表达。将ALK 4单倍缺陷（ALK 4 +/-）小鼠和野生型（WT）同窝小鼠随机分为假手术组和MI组。测量炎症细胞因子和趋化因子。分别于术后第3、7天行超声心动图和心内电生理检查。还在来自ALK 4 +/-小鼠和WT同窝仔的LPS或IL-4刺激的骨髓源性巨噬细胞（BMDM）中检测到ALK 4表达和炎症细胞因子。结果：心肌梗死患者外周血单核细胞ALK 4基因表达高于健康人。与WT同窝小鼠相比，ALK 4 +/-小鼠中急性心肌损伤后的心脏炎症和室性心律失常的脆弱性显著减轻。MI后第3天，与WT同窝小鼠相比，ALK 4 +/-小鼠中M1巨噬细胞的水平降低，而MI后第7天M2巨噬细胞的水平升高。从ALK 4 +/-小鼠分离的BMDM显示在低氧条件下LPS刺激后促炎细胞因子的分泌减少，并且在IL-4刺激后抗炎细胞因子的分泌增加。因此，ALK 4的单倍缺陷可能是MI后阶段炎症反应减少的原因。结论：ALK 4单倍缺陷减少心脏炎症，改善心脏功能，并最终降低MI后炎症阶段室性心律失常的脆弱性。
Background: 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. Methods: 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 3rd day and the 7th 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. Results: 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 3rd 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 7th 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. Conclusions: ALK4 haplodeficiency reduces cardiac inflammation, improves cardiac function, and finally reduces the vulnerability of ventricular arrhythmia in the inflammatory stage after MI.