RNA Splicing of the Abi1 Gene by MBNL1 contributes to macrophage‐like phenotype modulation of vascular smooth muscle cell during atherogenesis. (23rd March 2021)

• Record Type: Journal Article
• Authors: Li, Yinan; Guo, Xiangjiang; Xue, Guanhua; Wang, Han; Wang, Yuli; Wang, Weilun; Yang, Shuofei; Ni, Qihong; Chen, Jiaquan; Lv, Lei; Zhao, Yiping; Ye, Meng; Zhang, Lan
• Is Part Of: Cell proliferation. Volume 54:Number 5(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-03-23
• Subjects: Abi1 -- alternative splicing -- macrophage‐like vascular smooth muscle cells -- MBNL1; Cell proliferation -- Periodicals; 571.84
• DOI: 10.1111/cpr.13023
• Languages: English
• ISSNs: 0960-7722

Abstract

Abstract: Background: 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. Methods: 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. Results: 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. Conclusion: Loss‐of‐function of MBNL1 activates VSMC‐M transdifferentiation to promote atherogenesis through regulating Abi1 RNA splicing. Abstract : 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.