Cardiology Department, Hunan Provincial People's Hospital, No. 61 West Jiefang Road, Furong District, ChangshaHunan, 410000, China.
Clinical Research Center for Heart Failure in Hunan Province, No. 61 West Jiefang Road, Furong District, Changsha, 410000, Hunan, China.
Sci Rep. 2023 Apr 11;13(1):5904. doi: 10.1038/s41598-023-32919-4.
The role of RNA N6-methyladenosine (m6A) modification in the regulation of the immune microenvironment in ischaemic cardiomyopathy (ICM) remains largely unclear. This study first identified differential m6A regulators between ICM and healthy samples, and then systematically evaluated the effects of m6A modification on the characteristics of the immune microenvironment in ICM, including the infiltration of immune cells, the human leukocyte antigen (HLA) gene, and HALLMARKS pathways. A total of seven key m6A regulators, including WTAP, ZCH3H13, YTHDC1, FMR1, FTO, RBM15 and YTHDF3, were identified using a random forest classifier. A diagnostic nomogram based on these seven key m6A regulators could effectively distinguish patients with ICM from healthy subjects. We further identified two distinct m6A modification patterns (m6A cluster-A and m6A cluster-B) that are mediated by these seven regulators. Meanwhile, we also noted that one m6A regulator, WTAP, was gradually upregulated, while the others were gradually downregulated in the m6A cluster-A vs. m6A cluster-B vs. healthy subjects. In addition, we observed that the degree of infiltration of the activated dendritic cells, macrophages, natural killer (NK) T cells, and type-17 T helper (Th17) cells gradually increased in m6A cluster-A vs. m6A cluster-B vs. healthy subjects. Furthermore, m6A regulators, including FTO, YTHDC1, YTHDF3, FMR1, ZC3H13, and RBM15 were significantly negatively correlated with the above-mentioned immune cells. Additionally, several differential HLA genes and HALLMARKS signalling pathways between the m6A cluster-A and m6A cluster-B groups were also identified. These results suggest that m6A modification plays a key role in the complexity and diversity of the immune microenvironment in ICM, and seven key m6A regulators, including WTAP, ZCH3H13, YTHDC1, FMR1, FTO, RBM15, and YTHDF3, may be novel biomarkers for the accurate diagnosis of ICM. Immunotyping of patients with ICM will help to develop immunotherapy strategies with a higher level of accuracy for patients with a significant immune response.
RNA N6-甲基腺苷（m6A）修饰在缺血性心肌病（ICM）免疫微环境调节中的作用尚不清楚。本研究首先鉴定了 ICM 与健康样本之间差异表达的 m6A 调控因子，然后系统评估了 m6A 修饰对 ICM 免疫微环境特征的影响，包括免疫细胞浸润、人类白细胞抗原（HLA）基因和 HALLMARKS 通路。使用随机森林分类器鉴定了七个关键的 m6A 调控因子，包括 WTAP、ZCH3H13、YTHDC1、FMR1、FTO、RBM15 和 YTHDF3。基于这七个关键 m6A 调控因子的诊断列线图可以有效地将 ICM 患者与健康受试者区分开来。我们进一步鉴定了两种由这七个调控因子介导的不同的 m6A 修饰模式（m6A 簇-A 和 m6A 簇-B）。同时，我们还注意到，在 m6A 簇-A 与 m6A 簇-B 与健康对照组中，一个 m6A 调控因子 WTAP 逐渐上调，而其他调控因子逐渐下调。此外，我们观察到激活的树突状细胞、巨噬细胞、自然杀伤（NK）T 细胞和 17 型辅助 T（Th17）细胞的浸润程度在 m6A 簇-A 中逐渐增加-A 与 m6A 簇-B 与健康受试者相比。此外，包括 FTO、YTHDC1、YTHDF3、FMR1、ZC3H13 和 RBM15 在内的 m6A 调控因子与上述免疫细胞呈显著负相关。此外，还鉴定了 m6A 簇-A 和 m6A 簇-B 组之间的几个差异 HLA 基因和 HALLMARKS 信号通路。这些结果表明，m6A 修饰在 ICM 免疫微环境的复杂性和多样性中起关键作用，WTAP、ZCH3H13、YTHDC1、FMR1、FTO、RBM15 和 YTHDF3 等七个关键 m6A 调控因子可能是 ICM 准确诊断的新型生物标志物。对 ICM 患者进行免疫分型有助于开发具有更高准确性的免疫治疗策略，以满足具有显著免疫反应的患者的需求。
