AMPKα1 deletion in myofibroblasts exacerbates post myocardial infarction fibrosis by a miR-125b and Connexin 43 mechanism. AMPKα1 deletion in myofibroblasts exacerbates post myocardial infarction fibrosis by a miR-125b and Connexin 43 mechanism

Myofibroblasts (MFs) are crucial components of the fibrotic remodeling after myocardial infarction (MI). We have previously demonstrated the centrality of AMPKα1 in post-MI remodeling. Here, we investigate the effects of MF-specific deletion of AMPKα1 on left ventricular (LV) adaptation following MI, and the underlying molecular mechanisms. Importantly, MF-restricted AMPKα1 conditional knockout (cKO) hearts exhibit exacerbated post-MI adverse LV remodeling and are characterized by exaggerated fibrotic response, compared to wild-type (WT) hearts. Myofibroblast proliferation significantly increases in cKO infarcted hearts, coincident with a significant reduction of Connexin 43 (Cx43) expression in MFs. Mechanistically, lack of AMPKα1 in MFs enhances miR-125b expression, which, in turn, downregulates Cx43. Collectively, our data demonstrate a cardinal role for MF-AMPKα1 in cardiac remodeling, as its lineage-specific inactivation accentuates fibrosis and LV dilatation following MI. The deleterious effects of MF-specific AMPKα1 deletion are mediated via Cx43, and its post-transcriptional regulation by miR-125b. Overall design: We investigated the impact of AMPKa1 invalidation on mRNA profile in cultured human cardiac fibroblasts. We used 5 replicates per group,

肌成纤维细胞（Myofibroblasts, MFs）是心肌梗死（myocardial infarction, MI）后纤维化重塑的关键组成部分。我们此前已证实AMP活化蛋白激酶α1（AMPKα1）在心肌梗死后重塑中的核心作用。本研究旨在探究肌成纤维细胞特异性缺失AMPKα1对心肌梗死后左心室（left ventricular, LV）重构适应的影响，及其潜在分子机制。值得注意的是，与野生型（wild-type, WT）心脏相比，肌成纤维细胞限制性AMPKα1条件性敲除（conditional knockout, cKO）模型心脏的心肌梗死后不良左心室重构更为严重，且纤维化反应显著增强。在条件性敲除的梗死心脏中，肌成纤维细胞增殖显著升高，同时肌成纤维细胞内连接蛋白43（Connexin 43, Cx43）的表达量显著降低。机制层面，肌成纤维细胞中AMPKα1的缺失会上调微小RNA-125b（miR-125b）的表达，进而下调连接蛋白43的表达。综上，我们的研究数据表明，肌成纤维细胞中的AMPKα1在心脏重塑中发挥核心作用：其谱系特异性失活会加剧心肌梗死后的纤维化与左心室扩张。肌成纤维细胞特异性AMPKα1缺失所产生的有害效应，是通过连接蛋白43及其被微小RNA-125b介导的转录后调控实现的。实验设计概述：本研究探究了AMPKα1失活对培养的人心肌成纤维细胞中mRNA表达谱的影响，每组设置5个生物学重复。