Department of Cardiology, The Second Affiliate Hospital of Xi'an Jiaotong University, Xi'an, China.
Department of Cardiology, The First Affiliate Hospital of Xi'an Jiaotong University, Xi'an, China.
Cell Death Dis. 2021 Aug 27;12(9):813. doi: 10.1038/s41419-021-04109-5.
Atrial fibrillation (AF) is an increasingly prevalent arrhythmia with significant health and socioeconomic impact. The underlying mechanism of AF is still not well understood. In this study, we sought to identify hub genes involved in AF, and explored their functions and underlying mechanisms based on bioinformatics analysis. Five microarray datasets in GEO were used to identify the differentially expressed genes (DEGs) by Robust Rank Aggregation (RRA), and hub genes were screened out using protein-protein interaction (PPI) network. AF model was established using a mixture of acetylcholine and calcium chloride (Ach-CaCl) by tail vein injection. We totally got 35 robust DEGs that mainly involve in extracellular matrix formation, leukocyte transendothelial migration, and chemokine signaling pathway. Among these DEGs, we identified three hub genes involved in AF, of which CXCL12/CXCR4 axis significantly upregulated in AF patients stands out as one of the most potent targets for AF prevention, and its effect on AF pathogenesis and underlying mechanisms were investigated in vivo subsequently with the specific CXCR4 antagonist AMD3100 (6 mg/kg). Our results demonstrated an elevated transcription and translation of CXCL12/CXCR4 axis in AF patients and mice, accompanied with the anabatic atrial inflammation and fibrosis, thereby providing the substrate for AF maintenance. Blocking its signaling via AMD3100 administration in AF model mice reduced AF inducibility and duration, partly ascribed to decreased atrial inflammation and structural remodeling. Mechanistically, these effects were achieved by reducing the recruitment of CD3+ T lymphocytes and F4/80+ macrophages, and suppressing the hyperactivation of ERK1/2 and AKT/mTOR signaling in atria of AF model mice. In conclusion, this study provides new evidence that antagonizing CXCR4 prevents the development of AF, and suggests that CXCL12/CXCR4 axis may be a potential therapeutic target for AF.
心房颤动（AF）是一种日益流行的心律失常，对健康和社会经济有重大影响。AF 的潜在机制仍未得到很好的理解。在这项研究中，我们试图确定与 AF 相关的枢纽基因，并基于生物信息学分析探索它们的功能和潜在机制。使用 Robust Rank Aggregation（RRA）从 GEO 中的五个微阵列数据集鉴定差异表达基因（DEGs），并使用蛋白质-蛋白质相互作用（PPI）网络筛选枢纽基因。通过尾静脉注射乙酰胆碱和氯化钙（Ach-CaCl）混合物建立 AF 模型。我们总共获得了 35 个稳健的 DEG，这些基因主要涉及细胞外基质形成、白细胞穿过内皮迁移和趋化因子信号通路。在这些 DEGs 中，我们鉴定出三个与 AF 相关的枢纽基因，其中 CXCL12/CXCR4 轴在 AF 患者中显著上调，是 AF 预防的最有效靶点之一，随后使用特定的 CXCR4 拮抗剂 AMD3100（6 mg/kg）在体内研究其对 AF 发病机制和潜在机制的影响。我们的结果表明，AF 患者和小鼠的 CXCL12/CXCR4 轴转录和翻译水平升高，伴随着心房炎症和纤维化的增加，为 AF 的维持提供了基础。在 AF 模型小鼠中通过 AMD3100 给药阻断其信号传导可降低 AF 的可诱导性和持续时间，部分归因于心房炎症和结构重塑的减少。在机制上，这些作用是通过减少 CD3+T 淋巴细胞和 F4/80+巨噬细胞的募集以及抑制 AF 模型小鼠心房中 ERK1/2 和 AKT/mTOR 信号的过度激活来实现的。总之，这项研究提供了新的证据，表明拮抗 CXCR4 可预防 AF 的发生，并表明 CXCL12/CXCR4 轴可能是 AF 的潜在治疗靶点。
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