RNA Splicing of the Abi1 Gene by MBNL1 contributes to macrophage-like phenotype modulation of vascular smooth muscle cell during atherogenesis.
RNA Splicing of the Abi1 Gene by MBNL1 contributes to macrophage-like phenotype modulation of vascular smooth muscle cell during atherogenesis.
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MBNL1 对 Abi1 基因的 RNA 剪接有助于动脉粥样硬化形成过程中血管平滑肌细胞的巨噬细胞样表型调节
DOI：
10.1111/cpr.13023
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发表时间：
2021-05
影响因子：
8.5
通讯作者：
Zhang L
中科院分区：
文献类型：
--
作者：
Li Y;Guo X;Xue G;Wang H;Wang Y;Wang W;Yang S;Ni Q;Chen J;Lv L;Zhao Y;Ye M;Zhang L
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发生中起重要作用。肌盲样剪接调节因子1 （MBNL1）是一种众所周知的剪接因子，与许多细胞过程有关。然而，MBNL1在VSMC巨噬细胞样转分化中的作用在很大程度上是未知的。在这项研究中，我们的目的是表征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相互作用子1 （Abi1）剪接变异体（Abi1‐e10和Abi1‐Δe10）的表达。研究了MBNL1诱导Abi1基因剪接的调控机制，以及Abi1剪接变异体介导的VSMC信号通路。在动脉粥样硬化患者动脉壁巨噬细胞样VSMC （VSMC - M）中发现MBNL1的缺失。体外和体内证据证实Abi1是MBNL1的靶基因之一。MBNL1的缺失显著诱导Abi1‐Δe10亚型的表达。与已知的Abi1基因的肌动蛋白组织活性相比，我们发现了Abi1‐Δe10的新作用，即Abi1‐Δe10独立于上游刺激激活Rac1并触发Rac1‐NOX1‐ROS通路，从而导致转录因子Kruppel‐like factor 4 （KLF4）的表达增加。虽然Abi1‐Δe10抑制收缩性VSMC生物标志物的表达和细胞收缩，但它刺激VSMC增殖、迁移和巨噬细胞样转分化。MBNL1功能缺失激活VSMC - M转分化，通过调节Abi1 RNA剪接促进动脉粥样硬化。MBNL1的缺失通过选择性剪接在动脉粥样硬化患者动脉壁巨噬细胞样VSMC （VSMC‐M）中显著诱导Abi1‐Δe10亚型的表达。研究人员发现了Abi1‐Δe10的一种新作用，即Abi1‐Δe10能够独立于上游刺激激活Rac1。Abi1‐Δe10触发Rac1‐NOX1‐ROS通路上调KLF4，从而抑制收缩性VSMC生物标志物表达和细胞收缩，刺激VSMC增殖、迁移和巨噬细胞样转分化。
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. Loss of MBNL1 significantly induces the Abi1‐Δe10 isoform expression by alternative splicing in the macrophage‐like VSMC (VSMC‐M) in artery wall from atherosclerosis patients. A novel action of Abi1‐Δe10, whereby Abi1‐Δe10 actives Rac1 independent of upstream stimulation, was discovered. Abi1‐Δe10 triggers the Rac1‐NOX1‐ROS pathway to upregulate KLF4, which results in inhibition of contractile VSMC biomarkers expression and cell contraction and stimulation VSMC proliferation, migration and macrophage‐like transdifferentiation.
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影响因子：
5.3
作者：
Andreeva, ER;Pugach, IM;Orekhov, AN
通讯作者：
Orekhov, AN
影响因子：
3.7
作者：
Dubielecka PM;Cui P;Xiong X;Hossain S;Heck S;Angelov L;Kotula L
通讯作者：
Kotula L
影响因子：
56.9
作者：
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通讯作者：
Thomson, James A.
影响因子：
5.3
作者：
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通讯作者：
Goff, SP
影响因子：
10.5
作者：
SHI, YG;ALIN, K;GOFF, SP
通讯作者：
GOFF, SP