m6A Modification of Profilin-1 in Vascular Smooth Muscle Cells Drives Phenotype Switching and Neointimal Hyperplasia via Activation of the p-ANXA2/STAT3 Pathway.

IF 7.4 1区 医学 Q1 HEMATOLOGY Arteriosclerosis, Thrombosis, and Vascular Biology Pub Date : 2024-11-07 DOI:10.1161/ATVBAHA.124.321399
Xiao-Fei Gao, Ai-Qun Chen, Hao-Yue Tang, Xiang-Quan Kong, Huan Zhang, Zhi-Mei Wang, Wei Lu, Li-Guo Wang, Feng Wang, Wen-Ying Zhou, Yue Gu, Guang-Feng Zuo, Zhen Ge, Jun-Jie Zhang, Shao-Liang Chen
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Abstract

Background: In-stent restenosis is characterized by a significant reduction in lumen diameter within the stented segment, primarily attributed to excessive proliferation of vascular smooth muscle cells (VSMCs) and neointimal hyperplasia. PFN1 (profilin-1), an actin-sequestering protein extensively studied in amyotrophic lateral sclerosis, remains less explored in neointimal hyperplasia.

Methods: Utilizing single-cell RNA sequencing alongside data from in-stent restenosis patients and various experimental in-stent restenosis models (swine, rats, and mice), we investigated the role of PFN1 in promoting VSMC phenotype switching and neointimal hyperplasia.

Results: Single-cell RNA sequencing of stenotic rat carotid arteries revealed a critical role for PFN1 in neointimal hyperplasia, a finding corroborated in stented swine coronary arteries, in-stent restenosis patients, PFN1SMC-IKO (SMC-specific PFN1 knockout) mice, and PFN1 overexpressed mice. PFN1 deletion was shown to suppress VSMC phenotype switching and neointimal hyperplasia in PFN1SMC-IKO mice subjected to a wire-injured model. To elucidate the observed discordance in PFN1 mRNA and protein levels, we identified that METTL3 (N6-methyladenosine methyltransferase) and YTHDF3 (N6-methyladenosine-specific reader) enhance PFN1 translation efficiency in an N6-methyladenosine-dependent manner, confirmed through experiments involving METTL3 knockout and YTHDF3 knockout mice. Furthermore, PFN1 was mechanistically found to interact with the phosphorylation of ANXA2 (annexin A2) by recruiting Src, promoting the phosphorylation of STAT3, a typical transcription factor known to induce VSMC phenotype switching.

Conclusions: This study unveils the significance of PFN1 N6-methyladenosine modification in VSMCs, demonstrating its role in promoting phenotype switching and neointimal hyperplasia through the activation of the p-ANXA2 (phospho-ANXA2)/STAT3 pathway.

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血管平滑肌细胞中 Profilin-1 的 m6A 修饰通过激活 p-ANXA2/STAT3 通路驱动表型转换和新内膜增生。
背景:支架内再狭窄的特点是支架段内的管腔直径明显缩小,主要原因是血管平滑肌细胞(VSMC)过度增殖和新内膜增生。PFN1(profilin-1)是一种肌动蛋白序列蛋白,在肌萎缩性脊髓侧索硬化症中被广泛研究,但在新内膜增生中的研究仍较少:利用单细胞 RNA 测序以及支架内再狭窄患者和各种实验性支架内再狭窄模型(猪、大鼠和小鼠)的数据,我们研究了 PFN1 在促进 VSMC 表型转换和新内膜增生中的作用:狭窄大鼠颈动脉的单细胞 RNA 测序显示 PFN1 在新内膜增生中起关键作用,这一发现在支架植入的猪冠状动脉、支架内再狭窄患者、PFN1SMC-IKO(SMC 特异性 PFN1 基因敲除)小鼠和 PFN1 过表达小鼠中得到证实。研究表明,PFN1 基因缺失能抑制 PFN1SMC-IKO 小鼠在钢丝损伤模型中 VSMC 表型转换和新内膜增生。为了阐明所观察到的 PFN1 mRNA 和蛋白质水平的不一致性,我们发现 METTL3(N6-甲基腺苷甲基转移酶)和 YTHDF3(N6-甲基腺苷特异性阅读器)以 N6-甲基腺苷依赖的方式提高了 PFN1 的翻译效率,这一点通过 METTL3 基因敲除和 YTHDF3 基因敲除小鼠的实验得到了证实。此外,研究还发现 PFN1 通过招募 Src 与 ANXA2(附件素 A2)的磷酸化相互作用,促进 STAT3 的磷酸化,STAT3 是一种典型的转录因子,已知可诱导 VSMC 表型转换:本研究揭示了 PFN1 N6-甲基腺苷修饰在 VSMCs 中的重要意义,证明了其通过激活 p-ANXA2(磷酸化 ANXA2)/STAT3 通路促进表型转换和新内膜增生的作用。
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来源期刊
CiteScore
15.60
自引率
2.30%
发文量
337
审稿时长
2-4 weeks
期刊介绍: The journal "Arteriosclerosis, Thrombosis, and Vascular Biology" (ATVB) is a scientific publication that focuses on the fields of vascular biology, atherosclerosis, and thrombosis. It is a peer-reviewed journal that publishes original research articles, reviews, and other scholarly content related to these areas. The journal is published by the American Heart Association (AHA) and the American Stroke Association (ASA). The journal was published bi-monthly until January 1992, after which it transitioned to a monthly publication schedule. The journal is aimed at a professional audience, including academic cardiologists, vascular biologists, physiologists, pharmacologists and hematologists.
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