Department of Emergency, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518003, Guangdong, P. R. China.
Department of Emergency, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120, Guangdong, P. R. China.
Mol Med. 2024 Jun 15;30(1):89. doi: 10.1186/s10020-024-00856-1.
Myocardial infarction (MI) leads to enhanced activity of cardiac fibroblasts (CFs) and abnormal deposition of extracellular matrix proteins, resulting in cardiac fibrosis. Tartrate-resistant acid phosphatase 5 (ACP5) has been shown to promote cell proliferation and phenotypic transition. However, it remains unclear whether ACP5 is involved in the development of cardiac fibrosis after MI. The present study aimed to investigate the role of ACP5 in post-MI fibrosis and its potential underlying mechanisms.
Clinical blood samples were collected to detect ACP5 concentration. Myocardial fibrosis was induced by ligation of the left anterior descending coronary artery. The ACP5 inhibitor, AubipyOMe, was administered by intraperitoneal injection. Cardiac function and morphological changes were observed on Day 28 after injury. Cardiac CFs from neonatal mice were extracted to elucidate the underlying mechanism in vitro. The expression of ACP5 was silenced by small interfering RNA (siRNA) and overexpressed by adeno-associated viruses to evaluate its effect on CF activation.
The expression of ACP5 was increased in patients with MI, mice with MI, and mice with Ang II-induced fibrosis in vitro. AubipyOMe inhibited cardiac fibrosis and improved cardiac function in mice after MI. ACP5 inhibition reduced cell proliferation, migration, and phenotypic changes in CFs in vitro, while adenovirus-mediated ACP5 overexpression had the opposite effect. Mechanistically, the classical profibrotic pathway of glycogen synthase kinase-3β (GSK3β)/β-catenin was changed with ACP5 modulation, which indicated that ACP5 had a positive regulatory effect. Furthermore, the inhibitory effect of ACP5 deficiency on the GSK3β/β-catenin pathway was counteracted by an ERK activator, which indicated that ACP5 regulated GSK3β activity through ERK-mediated phosphorylation, thereby affecting β-catenin degradation.
ACP5 may influence the proliferation, migration, and phenotypic transition of CFs, leading to the development of myocardial fibrosis after MI through modulating the ERK/GSK3β/β-catenin signaling pathway.
心肌梗死（MI）导致心肌成纤维细胞（CFs）活性增强和细胞外基质蛋白异常沉积，导致心肌纤维化。耐酒石酸酸性磷酸酶 5（ACP5）已被证明可促进细胞增殖和表型转化。然而，ACP5 是否参与 MI 后心脏纤维化的发展仍不清楚。本研究旨在探讨 ACP5 在 MI 后纤维化中的作用及其潜在的作用机制。
收集临床血液样本以检测 ACP5 浓度。结扎左前降支冠状动脉诱导心肌纤维化。通过腹腔注射给予 ACP5 抑制剂 AubipyOMe。损伤后第 28 天观察心功能和形态变化。从小鼠分离心肌成纤维细胞以阐明体外潜在机制。通过小干扰 RNA（siRNA）沉默 ACP5 的表达，并通过腺相关病毒过表达来评估其对 CF 激活的影响。
MI 患者、MI 小鼠和体外 Ang II 诱导纤维化的小鼠中 ACP5 的表达增加。AubipyOMe 抑制 MI 后小鼠的心肌纤维化并改善心功能。ACP5 抑制可减少 CFs 的体外增殖、迁移和表型改变，而腺病毒介导的 ACP5 过表达则有相反的效果。机制上，通过 ACP5 调节改变了经典的糖原合酶激酶-3β（GSK3β）/β-连环蛋白的致纤维化途径，表明 ACP5 具有正调节作用。此外，ACP5 缺乏对 GSK3β/β-连环蛋白途径的抑制作用被 ERK 激活剂抵消，表明 ACP5 通过 ERK 介导的磷酸化调节 GSK3β 活性，从而影响β-连环蛋白的降解。
ACP5 可能通过调节 ERK/GSK3β/β-连环蛋白信号通路影响 CFs 的增殖、迁移和表型转化，导致 MI 后心肌纤维化的发生。
