Xinjiang Key Laboratory of Cardiac Electrophysiology and Cardiac Remodeling, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.
Cardiac Pacing and Electrophysiology Department, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.
FASEB J. 2024 Sep;38(18):e70068. doi: 10.1096/fj.202400546RR.
Atrial fibrosis plays a critical role in the pathogenesis of atrial fibrillation (AF). Monocyte chemotactic protein-induced protein-1 (MCPIP1), recognized as a functional ribonuclease (RNase), exacerbates cardiac remodeling and contributes to a range of cardiovascular diseases. However, the involvement of MCPIP1 in atrial fibrosis and development of AF, along with its underlying biological mechanisms, remains poorly understood. This study demonstrated that knockdown of MCPIP1 significantly reduced AF inducibility, decreased left atrial diameter, and ameliorated atrial fibrosis, coinciding with reduced FRAT1/2/Wnt/β-catenin signaling. Furthermore, the MCPIP1-D141N mutation attenuated AF vulnerability and atrial remodeling compared to MCPIP1 overexpression in an acetylcholine and calcium chloride (ACh-CaCl)-induced rat model of AF. Conversely, overexpression of FRAT1/2 partially reversed the cardioprotective effects of MCPIP1-D141N mutation. Using H9C2 cell lines, we observed that MCPIP1 may induce a transcriptional effect that downregulates miR-26a-5p expression, and luciferase and RNA immunoprecipitation (RIP) assays substantiated the direct interaction between miR-26a-5p and FRAT1/2. Moreover, overexpression of miR-26a-5p countered MCPIP1-induced atrial remodeling and attenuated the progression of AF. In conclusion, these findings indicate that MCPIP1 facilitates atrial remodeling and the progression of AF by exacerbating miR-26a-5p/FRAT/Wnt axis-mediated atrial fibrosis through its RNase activity in an ACh-CaCl-induced rat model of AF.
心房纤维化在心房颤动（AF）的发病机制中起着关键作用。单核细胞趋化蛋白诱导蛋白-1（MCPIP1），作为一种功能性核糖核酸酶（RNase），可加重心脏重构，并导致多种心血管疾病。然而，MCPIP1 在心房纤维化和 AF 发展中的作用及其潜在的生物学机制仍知之甚少。本研究表明，MCPIP1 的敲低显著降低了 AF 的易感性，减小了左心房直径，并改善了心房纤维化，同时 FRAT1/2/Wnt/β-连环蛋白信号也减少了。此外，与 MCPIP1 过表达相比，MCPIP1-D141N 突变在乙酰胆碱和氯化钙（ACh-CaCl）诱导的 AF 大鼠模型中减弱了 AF 易感性和心房重构。相反，FRAT1/2 的过表达部分逆转了 MCPIP1-D141N 突变的心脏保护作用。在 H9C2 细胞系中，我们观察到 MCPIP1 可能诱导一种下调 miR-26a-5p 表达的转录效应，并且荧光素酶和 RNA 免疫沉淀（RIP）测定证实了 miR-26a-5p 与 FRAT1/2 之间的直接相互作用。此外，miR-26a-5p 的过表达可逆转 MCPIP1 诱导的心房重构，并减轻 AF 的进展。总之，这些发现表明，MCPIP1 通过其在 ACh-CaCl 诱导的 AF 大鼠模型中的 RNase 活性加剧了 miR-26a-5p/FRAT/Wnt 轴介导的心房纤维化，从而促进了心房重构和 AF 的进展。
