Department of Vascular Surgery, Renji Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
Cell Prolif. 2021 May;54(5):e13023. doi: 10.1111/cpr.13023. Epub 2021 Mar 23.
Vascular smooth muscle cells (VSMC) switch to macrophage-like cells after cholesterol loading, and this change may play an important role in atherogenesis. Muscleblind-like splicing regulator 1 (MBNL1) is a well-known splicing factor that has been implicated in many cellular processes. However, the role of MBNL1 in VSMC macrophage-like transdifferentiation is largely unknown. In this study, we aim to characterize the role of MBNL1-induced gene splicing during atherogenesis.
The expression of MBNL1 and Abelson interactor 1 (Abi1) splice variants (Abi1-e10 and Abi1-Δe10) was compared between artery tissues from healthy donors and atherosclerosis patients. Regulatory mechanisms of MBNL1-induced Abi1 gene splicing were studied, and the signal pathways mediated by Abi1 splice variants were investigated in VSMC.
Loss of MBNL1 was found in the macrophage-like VSMC (VSMC-M) in artery wall from atherosclerosis patients. In vitro and in vivo evidence confirmed that Abi1 is one of the MBNL1 target genes. Loss of MBNL1 significantly induces the Abi1-Δe10 isoform expression. Compared to the known actin organization activities of the Abi1 gene, we discovered a novel action of Abi1-Δe10, whereby Abi1-Δe10 activates Rac1 independent of upstream stimulation and triggers the Rac1-NOX1-ROS pathway, which results in increased expression of transcription factor Kruppel-like factor 4 (KLF4). While Abi1-Δe10 inhibits contractile VSMC biomarkers expression and cell contraction, it stimulates VSMC proliferation, migration and macrophage-like transdifferentiation.
Loss-of-function of MBNL1 activates VSMC-M transdifferentiation to promote atherogenesis through regulating Abi1 RNA splicing.
血管平滑肌细胞（VSMC）在胆固醇负荷后转变为巨噬细胞样细胞，这种变化可能在动脉粥样硬化的发生中起重要作用。肌肉盲样剪接调节因子 1（MBNL1）是一种众所周知的剪接因子，它参与了许多细胞过程。然而，MBNL1 在 VSMC 向巨噬细胞样转化中的作用在很大程度上尚不清楚。在这项研究中，我们旨在描述 MBNL1 诱导的基因剪接在动脉粥样硬化发生中的作用。
比较了健康供体和动脉粥样硬化患者动脉组织中 MBNL1 和 Abelson 相互作用因子 1（Abi1）剪接变体（Abi1-e10 和 Abi1-Δe10）的表达。研究了 MBNL1 诱导的 Abi1 基因剪接的调节机制，并研究了 Abi1 剪接变体在 VSMC 中的信号通路。
在动脉粥样硬化患者的动脉壁中的巨噬细胞样 VSMC（VSMC-M）中发现 MBNL1 丢失。体内外证据证实，Abi1 是 MBNL1 的靶基因之一。MBNL1 的缺失显著诱导 Abi1-Δe10 异构体的表达。与 Abi1 基因已知的肌动蛋白组织活性相比，我们发现了 Abi1-Δe10 的一种新作用，即 Abi1-Δe10 在没有上游刺激的情况下独立激活 Rac1，并触发 Rac1-NOX1-ROS 通路，导致转录因子 Kruppel 样因子 4（KLF4）的表达增加。虽然 Abi1-Δe10 抑制收缩型 VSMC 标志物的表达和细胞收缩，但它刺激 VSMC 的增殖、迁移和巨噬细胞样转化。
MBNL1 的功能丧失通过调节 Abi1 RNA 剪接激活 VSMC-M 转化，从而促进动脉粥样硬化的发生。
