We have previously demonstrated that systemic AMP-activated protein kinase α1 (AMPKα1) invalidation enhanced adverse LV remodelling by increasing fibroblast proliferation, while myodifferentiation and scar maturation were impaired. We thus hypothesised that fibroblastic AMPKα1 was a key signalling element in regulating fibrosis in the infarcted myocardium and an attractive target for therapeutic intervention. The present study investigates the effects of myofibroblast (MF)-specific deletion of AMPKα1 on left ventricular (LV) adaptation following myocardial infarction (MI), and the underlying molecular mechanisms. MF-restricted AMPKα1 conditional knockout (cKO) mice were subjected to permanent ligation of the left anterior descending coronary artery. cKO hearts exhibit exacerbated post-MI adverse LV remodelling and are characterised by exaggerated fibrotic response, compared to wild-type (WT) hearts. Cardiac fibroblast proliferation and MF content significantly increase in cKO infarcted hearts, coincident with a significant reduction of connexin 43 (Cx43) expression in MFs. Mechanistically, AMPKα1 influences Cx43 expression by both a transcriptional and a post-transcriptional mechanism involving miR-125b-5p. Collectively, our data demonstrate that MF-AMPKα1 functions as a master regulator of cardiac fibrosis and remodelling and might constitute a novel potential target for pharmacological anti-fibrotic applications.

我们之前已经证明，全身性 AMP 激活蛋白激酶 α1 (AMPKα1) 失效通过增加成纤维细胞增殖而增强不良左心室重塑，同时肌分化和疤痕成熟受到损害。因此，我们假设成纤维细胞 AMPKα1 是调节梗塞心肌纤维化的关键信号元件，也是治疗干预的有吸引力的靶点。本研究探讨肌成纤维细胞 (MF) 特异性缺失 AMPKα1 对心肌梗死 (MI) 后左心室 (LV) 适应的影响及其潜在的分子机制。对 MF 限制性 AMPKα1 条件敲除 (cKO) 小鼠进行左冠状动脉前降支永久结扎。与野生型 (WT) 心脏相比，cKO 心脏表现出加剧的 MI 后不良左心室重塑，并以过度的纤维化反应为特征。 cKO 梗塞心脏中心脏成纤维细胞增殖和 MF 含量显着增加，同时 MF 中连接蛋白 43 (Cx43) 表达显着减少。从机制上讲，AMPKα1 通过涉及 miR-125b-5p 的转录和转录后机制影响 Cx43 表达。总的来说，我们的数据表明 MF-AMPKα1 作为心脏纤维化和重构的主要调节因子发挥作用，并可能构成药理抗纤维化应用的新的潜在靶点。