Novel Pathological Role of hnRNPA1 (Heterogeneous Nuclear Ribonucleoprotein A1) in Vascular Smooth Muscle Cell Function and Neointima Hyperplasia.
Novel Pathological Role of hnRNPA1 (Heterogeneous Nuclear Ribonucleoprotein A1) in Vascular Smooth Muscle Cell Function and Neointima Hyperplasia.
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hnRNPA1（异质核核糖核蛋白 A1）在血管平滑肌细胞功能和新内膜增生中的新病理作用。
DOI：
10.1161/atvbaha.117.310020
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发表时间：
2017-11
期刊：
影响因子：
--
通讯作者：
Xiao Q
中科院分区：
文献类型：
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作者：
Zhang L;Chen Q;An W;Yang F;Maguire EM;Chen D;Zhang C;Wen G;Yang M;Dai B;Luong LA;Zhu J;Xu Q;Xiao Q
补充数字内容可在文本中找到。hnRNPA 1（heterogeneous nuclear ribonucleoprotein A1）在基因表达中起着多种作用。然而，很少有人知道hnRNPA 1的功能参与血管平滑肌细胞（VSMC）的功能和新生内膜增生。在这项研究中，我们试图研究hnRNPA 1在VSMC功能，损伤诱导的血管重塑和人类动脉粥样硬化病变的背景下的功能作用，以及辨别所涉及的分子机制。hnRNPA 1表达水平在血管平滑肌细胞表型转换和导丝损伤诱导的新生内膜损伤形成过程中受到一致调节。功能研究表明，VSMC特异性基因的表达，增殖和迁移的hnRNPA 1调节。我们的数据表明，hnRNPA 1通过调节IQGAP 1（IQ motif containing GT3 activating protein 1）对VSMC功能发挥作用。hnRNPA 1通过上调microRNA-124（miR-124）和与IQGAP 1基因的AU富集元件结合两种机制调节IQGAP 1 mRNA的降解。进一步的证据表明，hnRNPA 1通过调节miR-124的生物合成上调miR-124，IQGAP 1是miR-124的真正靶基因。重要的是，hnRNPA 1的异位过表达大大降低了血管平滑肌细胞的增殖，抑制了钢丝损伤的颈动脉中新生内膜的形成。最后，在人类动脉粥样硬化病变中观察到hnRNPA 1和miR-124的较低表达水平，而IQGAP 1的较高表达水平。我们的数据显示，hnRNPA 1是新生内膜增生背景下VSMC功能和行为的关键调节因子，hnRNPA 1/miR-124/IQGAP 1调节轴代表了预防心血管疾病的新治疗靶点。
Supplemental Digital Content is available in the text. hnRNPA1 (heterogeneous nuclear ribonucleoprotein A1) plays a variety of roles in gene expression. However, little is known about the functional involvement of hnRNPA1 in vascular smooth muscle cell (VSMC) function and neointima hyperplasia. In this study, we have attempted to investigate the functional roles of hnRNPA1 in the contexts of VSMC function, injury-induced vessel remodeling, and human atherosclerotic lesions, as well as discern the molecular mechanisms involved. hnRNPA1 expression levels were consistently modulated during VSMC phenotype switching and neointimal lesion formation induced by wire injury. Functional studies showed that VSMC-specific gene expression, proliferation, and migration were regulated by hnRNPA1. Our data show that hnRNPA1 exerts its effects on VSMC functions through modulation of IQGAP1 (IQ motif containing GTPase activating protein 1). Mechanistically, hnRNPA1 regulates IQGAP1 mRNA degradation through 2 mechanisms: upregulating microRNA-124 (miR-124) and binding to AU-rich element of IQGAP1 gene. Further evidence suggests that hnRNPA1 upregulates miR-124 by modulating miR-124 biogenesis and that IQGAP1 is the authentic target gene of miR-124. Importantly, ectopic overexpression of hnRNPA1 greatly reduced VSMC proliferation and inhibited neointima formation in wire-injured carotid arteries. Finally, lower expression levels of hnRNPA1 and miR-124, while higher expression levels of IQGAP1, were observed in human atherosclerotic lesions. Our data show that hnRNPA1 is a critical regulator of VSMC function and behavior in the context of neointima hyperplasia, and the hnRNPA1/miR-124/IQGAP1 regulatory axis represents a novel therapeutic target for the prevention of cardiovascular diseases.