Ruan Renjie, Zhang Yunrui
Department of Cardiology, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325200, People's Republic of China.
J Inflamm Res. 2025 May 27;18:6821-6830. doi: 10.2147/JIR.S487828. eCollection 2025.
Coronary heart disease (CHD) ranks as the primary cause of global morbidity and mortality. Despite of the progress in exploring risk factors and developing medications, considerable residual risk persists. In recent years, epigenetic regulation has emerged as a critical regulatory mechanism across various diseases. This study aimed to investigate the effects of methyltransferase-like protein 16 (METTL16) on CHD and the potential molecular mechanisms.
A CHD mouse model was established and treated with METTL16 depletion treatment. The METTL16 RNA level was measured by qPCR assay. Cardiac function was estimated by using echocardiography. Tissue damage and cardiac fibrosis were analyzed by deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and Masson's trichrome staining. The blood samples were collected to measure lipid levels and cardiac function biomarkers. Vascular smooth muscle cells (VSMCs) were isolated, and cell viability and proliferation were detected by cell counting kit 8 (CCK-8) and colony formation assay. Cell apoptosis was determined by flow cytometry. Expression of apoptosis biomarkers was detected by Western blotting assay. The m6A enrichment on TET2 mRNA was determined by methylated RNA immunoprecipitation (MeRIP) assay and cross-Linking Immunoprecipitation and qPCR (CLIP-qPCR).
We observed elevated expression of METTL16 in cardiac tissues of CHD mice, and knockdown of METTL16 notably recovered the cardiac function, alleviated cardiac fibrosis, and decreased lipid levels. Knockdown of METTL16 suppressed VSMC proliferation and elevated cell apoptosis. METTL16 directly modulated the m6A enrichment on TET2 mRNA, and overexpression of TET2 could reverse the inhibitory effects of siMETTL16 on VSMC proliferation.
METTL16 affects the cardiac damage and function during CHD via epigenetically modulating the m6A modification of TET2.
冠心病（CHD）是全球发病和死亡的主要原因。尽管在探索危险因素和开发药物方面取得了进展，但仍存在相当大的残余风险。近年来，表观遗传调控已成为各种疾病的关键调控机制。本研究旨在探讨甲基转移酶样蛋白16（METTL16）对冠心病的影响及其潜在的分子机制。
建立冠心病小鼠模型并进行METTL16缺失处理。通过qPCR检测METTL16 RNA水平。使用超声心动图评估心脏功能。通过脱氧核苷酸末端转移酶dUTP缺口末端标记（TUNEL）和Masson三色染色分析组织损伤和心脏纤维化。采集血样以测量血脂水平和心脏功能生物标志物。分离血管平滑肌细胞（VSMC），并通过细胞计数试剂盒8（CCK-8）和集落形成试验检测细胞活力和增殖。通过流式细胞术测定细胞凋亡。通过蛋白质免疫印迹法检测凋亡生物标志物的表达。通过甲基化RNA免疫沉淀（MeRIP）试验以及交联免疫沉淀和qPCR（CLIP-qPCR）测定TET2 mRNA上的m6A富集情况。
我们观察到冠心病小鼠心脏组织中METTL16表达升高，敲低METTL16可显著恢复心脏功能，减轻心脏纤维化，并降低血脂水平。敲低METTL16可抑制VSMC增殖并增加细胞凋亡。METTL16直接调节TET2 mRNA上的m6A富集，过表达TET2可逆转siMETTL16对VSMC增殖的抑制作用。
METTL16通过表观遗传调控TET2的m6A修饰影响冠心病期间的心脏损伤和功能。
