Department of Cardiology, The Central Hospital of ShaoYang, No. 36 QianYuan Lane, Daxiang District, Shaoyang, 422000, Hunan, China.
Cardiology Department, Hunan Provincial People's Hospital, No.61 West Jiefang Road, Furong District, Changsha, 410000, Hunan, China.
Sci Rep. 2024 Oct 9;14(1):23577. doi: 10.1038/s41598-024-75115-8.
Mitochondrial dysfunction and immune cell infiltration play crucial yet incompletely understood roles in the pathogenesis of calcific aortic valve disease (CAVD). This study aimed to identify immune-related mitochondrial genes critical to the pathological process of CAVD using multiomics approaches. The CIBERSORT algorithm was employed to evaluate immune cell infiltration characteristics in CAVD patients. An integrative analysis combining weighted gene coexpression network analysis (WGCNA), machine learning, and summary data-based Mendelian randomization (SMR) was performed to identify key mitochondrial genes implicated in CAVD. Spearman's rank correlation analysis was also performed to assess the relationships between key mitochondrial genes and infiltrating immune cells. Compared with those in normal aortic valve tissue, an increased proportion of M0 macrophages and resting memory CD4 T cells, along with a decreased proportion of plasma cells and activated dendritic cells, were observed in CAVD patients. Additionally, eight key mitochondrial genes associated with CAVD, including PDK4, LDHB, SLC25A36, ALDH9A1, ECHDC2, AUH, ALDH2, and BNIP3, were identified through the integration of WGCNA and machine learning methods. Subsequent SMR analysis, incorporating multiomics data, such as expression quantitative trait loci (eQTLs) and methylation quantitative trait loci (mQTLs), revealed a significant causal relationship between ALDH9A1 expression and a reduced risk of CAVD. Moreover, ALDH9A1 expression was inversely correlated with M0 macrophages and positively correlated with M2 macrophages. These findings suggest that increased ALDH9A1 expression is significantly associated with a reduced risk of CAVD and that it may exert its protective effects by modulating mitochondrial function and immune cell infiltration. Specifically, ALDH9A1 may contribute to the shift from M0 macrophages to anti-inflammatory M2 macrophages, potentially mitigating the pathological progression of CAVD. In conclusion, ALDH9A1 represents a promising molecular target for the diagnosis and treatment of CAVD. However, further validation through in vivo and n vitro studies is necessary to confirm its role in CAVD pathogenesis and therapeutic potential.
线粒体功能障碍和免疫细胞浸润在钙化性主动脉瓣疾病（CAVD）的发病机制中起着至关重要但尚未完全理解的作用。本研究旨在使用多组学方法鉴定与 CAVD 病理过程相关的免疫相关线粒体基因。使用 CIBERSORT 算法评估 CAVD 患者的免疫细胞浸润特征。通过整合加权基因共表达网络分析（WGCNA）、机器学习和基于汇总数据的孟德尔随机化（SMR）分析，鉴定与 CAVD 相关的关键线粒体基因。还进行了 Spearman 秩相关分析，以评估关键线粒体基因与浸润免疫细胞之间的关系。与正常主动脉瓣组织相比，CAVD 患者中 M0 巨噬细胞和静息记忆 CD4 T 细胞的比例增加，浆细胞和活化树突状细胞的比例减少。此外，通过 WGCNA 和机器学习方法的整合，鉴定出与 CAVD 相关的 8 个关键线粒体基因，包括 PDK4、LDHB、SLC25A36、ALDH9A1、ECHDC2、AUH、ALDH2 和 BNIP3。随后，通过纳入多组学数据（如表达数量性状基因座（eQTL）和甲基化数量性状基因座（mQTL））的 SMR 分析，揭示了 ALDH9A1 表达与 CAVD 风险降低之间存在显著的因果关系。此外，ALDH9A1 的表达与 M0 巨噬细胞呈负相关，与 M2 巨噬细胞呈正相关。这些发现表明，ALDH9A1 表达增加与 CAVD 风险降低显著相关，其可能通过调节线粒体功能和免疫细胞浸润发挥保护作用。具体而言，ALDH9A1 可能有助于从 M0 巨噬细胞向抗炎 M2 巨噬细胞的转变，从而可能减轻 CAVD 的病理进展。总之，ALDH9A1 代表了 CAVD 诊断和治疗的有前途的分子靶点。然而，需要通过体内和体外研究进一步验证其在 CAVD 发病机制和治疗潜力中的作用。
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