Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Youzheng Street 23#, Nangang District, Harbin, 150001, Heilongjiang, China.
NHC Key Laboratory of Cell Translation, Harbin Medical University, Harbin, 150001, Heilongjiang, China.
J Transl Med. 2022 Sep 5;20(1):407. doi: 10.1186/s12967-022-03617-y.
Atrial fibrosis plays a critical role in the development of atrial fibrillation (AF). Exosomes are a promising cell-free therapeutic approach for the treatment of AF. The purposes of this study were to explore the mechanisms by which exosomes derived from atrial myocytes regulate atrial remodeling and to determine whether their manipulation facilitates the therapeutic modulation of potential fibrotic abnormalities during AF.
We isolated exosomes from atrial myocytes and patient serum, and microRNA (miRNA) sequencing was used to analyze exosomal miRNAs in exosomes derived from atrial myocytes and patient serum. mRNA sequencing and bioinformatics analyses corroborated the key genes that were direct targets of miR-210-3p.
The miRNA sequencing analysis identified that miR-210-3p expression was significantly increased in exosomes from tachypacing atrial myocytes and serum from patients with AF. In vitro, the miR-210-3p inhibitor reversed tachypacing-induced proliferation and collagen synthesis in atrial fibroblasts. Accordingly, miR-210-3p knock out (KO) reduced the incidence of AF and ameliorated atrial fibrosis induced by Ang II. The mRNA sequencing analysis and dual-luciferase reporter assay showed that glycerol-3-phosphate dehydrogenase 1-like (GPD1L) is a potential target gene of miR-210-3p. The functional analysis suggested that GPD1L regulated atrial fibrosis via the PI3K/AKT signaling pathway. In addition, silencing GPD1L in atrial fibroblasts induced cell proliferation, and these effects were reversed by a PI3K inhibitor (LY294002).
Atrial myocyte-derived exosomal miR-210-3p promoted cell proliferation and collagen synthesis by inhibiting GPD1L in atrial fibroblasts. Preventing pathological crosstalk between atrial myocytes and fibroblasts may be a novel target to ameliorate atrial fibrosis in patients with AF.
心房纤维化在心房颤动（AF）的发展中起着关键作用。外泌体是治疗 AF 的一种很有前途的无细胞治疗方法。本研究旨在探讨心肌细胞来源的外泌体调节心房重构的机制，并确定是否通过操纵它们有助于治疗调节 AF 期间潜在的纤维化异常。
我们从心房心肌细胞和患者血清中分离出外泌体，并使用 microRNA（miRNA）测序分析心肌细胞来源的外泌体和患者血清中外泌体中的 miRNA。mRNA 测序和生物信息学分析证实了 miR-210-3p 的直接靶基因。
miRNA 测序分析表明，快速起搏心房心肌细胞来源的外泌体和 AF 患者血清中 miR-210-3p 的表达显著增加。在体外，miR-210-3p 抑制剂逆转了快速起搏诱导的心房成纤维细胞增殖和胶原合成。相应地，miR-210-3p 敲除（KO）减少了 Ang II 诱导的 AF 发生率和心房纤维化。mRNA 测序分析和双荧光素酶报告基因检测表明，甘油-3-磷酸脱氢酶 1 样（GPD1L）是 miR-210-3p 的潜在靶基因。功能分析表明，GPD1L 通过 PI3K/AKT 信号通路调节心房纤维化。此外，在心房成纤维细胞中沉默 GPD1L 诱导细胞增殖，这些效应被 PI3K 抑制剂（LY294002）逆转。
心肌细胞来源的外泌体 miR-210-3p 通过抑制心房成纤维细胞中的 GPD1L 促进细胞增殖和胶原合成。预防心房肌细胞与成纤维细胞之间的病理性串扰可能是改善 AF 患者心房纤维化的新靶点。
