Wang Xu, Liu Yihui, Liu Heng, Zhang Mengfan, Yang Lida, Dinislam Khuzin, Hu Hongbo, Xiao Dan, Yang Huan, Zhang Ying
Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin, China; The State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), and the Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, Harbin, China; Department of Microbiology, School of Basic Medical Sciences, WU Lien-Teh Institute, Harbin Medical University, Harbin, China.
The Second Affiliated Hospital of Harbin Medical University, Harbin, China.
J Biol Chem. 2025 Jul 2;301(8):110448. doi: 10.1016/j.jbc.2025.110448.
Cardiac fibrosis is a pathological hallmark of various cardiovascular disorders. Accumulating evidence has demonstrated that fibroblasts transform into myofibroblasts during the occurrence of cardiac fibrosis, but the mechanism remains incompletely understood. This study aims to investigate the relevance of MTA3 as a potential therapeutic target for cardiac fibrosis. The myocardial infarction model was established by ligating the left coronary artery of C57BL6 mice, and myocardial fibrosis was measured by cardiac ultrasound and Sirius red staining of myocardium. MTA3 overexpression plasmid was constructed and transfected into primary fibroblasts, immunofluorescence, Western blot and qRT-PCR were used to detect the expression of MTA3, α-SMA, and Collagen I. RNAi was used to interfere with the downstream potential target gene E2F1. SB203580, a specific inhibitor of p38 MAPK, reduced the levels of phosphorylated p38 MAPK (p-p38) by inhibiting p38 MAPK activity, and allowed assessment of MTA3-induced fibroblast to myofibroblast transformation. The expression of MTA3 was reduced in fibrotic myocardium. Overexpression of MTA3 could restore cardiac function. During the transformation process of cardiac fibroblasts into myofibroblasts, the expression of MTA3 was downregulated. After overexpression of MTA3, the mRNA and protein levels of α-SMA and Collagen I were significantly reduced. When E2F1 was disrupted, the mRNA and protein levels of α-SMA and Collagen I were downregulated. Inhibition of p-p38 MAPK expression by SB203580 ameliorated myocardial fibrosis. MTA3 regulates the transformation of fibroblast into myofibroblast by p38 MAPK-E2F1 signaling pathway, and MTA3 may become a potential target for treating cardiac fibrosis.
心脏纤维化是各种心血管疾病的病理标志。越来越多的证据表明，在心脏纤维化发生过程中，成纤维细胞会转变为肌成纤维细胞，但其机制仍未完全阐明。本研究旨在探讨MTA3作为心脏纤维化潜在治疗靶点的相关性。通过结扎C57BL6小鼠的左冠状动脉建立心肌梗死模型，并通过心脏超声和心肌天狼星红染色检测心肌纤维化。构建MTA3过表达质粒并转染至原代成纤维细胞，采用免疫荧光、蛋白质免疫印迹和qRT-PCR检测MTA3、α-SMA和I型胶原蛋白的表达。利用RNA干扰技术干扰下游潜在靶基因E2F1。p38丝裂原活化蛋白激酶（MAPK）的特异性抑制剂SB203580通过抑制p38 MAPK活性降低磷酸化p38 MAPK（p-p38）水平，并用于评估MTA3诱导的成纤维细胞向肌成纤维细胞的转化。纤维化心肌中MTA3的表达降低。MTA3过表达可恢复心脏功能。在心脏成纤维细胞向肌成纤维细胞的转化过程中，MTA3的表达下调。MTA3过表达后，α-SMA和I型胶原蛋白的mRNA和蛋白水平显著降低。当E2F1被干扰时，α-SMA和I型胶原蛋白的mRNA和蛋白水平下调。SB203580抑制p-p38 MAPK表达可改善心肌纤维化。MTA3通过p38 MAPK-E2F1信号通路调节成纤维细胞向肌成纤维细胞的转化，MTA3可能成为治疗心脏纤维化的潜在靶点。
