Novel Pathological Role of hnRNPA1 (Heterogeneous Nuclear Ribonucleoprotein A1) in Vascular Smooth Muscle Cell Function and Neointima Hyperplasia

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 37; no. 11; pp. 2182 - 2194
• Main Authors: Zhang, Li, Chen, Qishan, An, Weiwei, Yang, Feng, Maguire, Eithne Margaret, Chen, Dan, Zhang, Cheng, Wen, Guanmei, Yang, Mei, Dai, Bin, Luong, Le Anh, Zhu, Jianhua, Xu, Qingbo, Xiao, Qingzhong
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 01.11.2017; Lippincott Williams & Wilkins
• Subjects: 3' Untranslated Regions; Animals; Carotid Artery Injuries - genetics; Carotid Artery Injuries - metabolism; Carotid Artery Injuries - pathology; Carotid Artery, Common - metabolism; Carotid Artery, Common - pathology; Cell Movement; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Gene Expression Regulation; Heterogeneous Nuclear Ribonucleoprotein A1; Heterogeneous-Nuclear Ribonucleoprotein Group A-B - genetics; Heterogeneous-Nuclear Ribonucleoprotein Group A-B - metabolism; Hyperplasia; Male; Mice; Mice, Inbred C57BL; MicroRNAs - genetics; MicroRNAs - metabolism; Muscle, Smooth, Vascular - injuries; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - pathology; Myocytes, Smooth Muscle - metabolism; Myocytes, Smooth Muscle - pathology; Neointima; ras GTPase-Activating Proteins - genetics; ras GTPase-Activating Proteins - metabolism; RNA Interference; Signal Transduction; Time Factors; Transfection; Translational Sciences; microRNAs; RNA; cell proliferation; neointima; cell migration; vascular smooth muscle cells; binding protein
• ISSN: 1079-5642; 1524-4636; 1524-4636
• DOI: 10.1161/ATVBAHA.117.310020

OBJECTIVE—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. APPROACH AND RESULTS—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 mechanismsupregulating 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. CONCLUSIONS—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.Arteriosclerosis, Thrombosis, and Vascular Biology is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.