Background RNA binding protein heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) plays various roles in transcriptional and posttranscriptional modulation of gene expression. Our previous study has demonstrated for the first time that hnRNPA1 plays an important role in vascular smooth muscle cell (VSMC) differentiation from stem cells in vitro and in vivo . However, little is known about the functional involvements of hnRNPA1 in VSMC functions and neointima hyperplasia.
Purpose In this study, we aimed to investigate the functional roles of hnRNPA1 in the contexts of VSMC functions, injury-induced vessel remodelling and human atherosclerotic lesions, and the molecular mechanisms involved.
Methods and results Studies used mouse aorta VSMCs showed that hnRNPA1 expression levels were consistently modulated during VSMC phenotype switching. Moreover, VSMCs with hnRNPA1 knockdown had an increased migratory and proliferative ability, but a reduced VSMC-specific gene expression level. Consistently, over-expression of hnRNPA1 significantly reduced VSMC migration and proliferation. Furthermore, our data shows that hnRNPA1 exerts its effects on VSMC functions through modulating IQ motif containing GTPase activating protein 1 (IQGAP1) gene, a well-known important regulator of VSMC migration and proliferation. Mechanistically, hnRNPA1 regulates IQGAP1 mRNA degradation through two mechanisms: upregulating miR-124 and AU-rich element (ARE). Further evidence suggests that hnRNPA1 up-regulates miR-124 through regulating miR-124 biogenesis, and that IQGAP1 is the authentic target gene of miR-124. Importantly, the expression levels of hnRNPA1 were significantly down-regulated during neointimal lesion formation induced by wire injury, suggesting a role for hnRNPA1 in vessel injury-induced neointimal development and progression. In accordance, perivascular ectopic overexpression of hnRNPA1 greatly reduced VSMC proliferation, and inhibited neointima formation in wire-injured carotid arteries. Translationally and consistently, lower expression levels of hnRNPA1 and miR-124, while higher expression levels of IQGAP1, were observed in human atherosclerotic lesions.
Conclusions We have identified hnRNPA1 as a critical regulator in VSMC functions and neointima hyperplasia. Our data provide new insight into the roles of hnRNPA1/miR-124/IQGAP1 regulatory axis in VSMC functions and the pathogenesis of neointima formation and/or angiographic restenosis, and aid the development of novel therapeutic agents for the prevention of these diseases.
- heterogeneous nuclear ribonucleoprotein A1
- vascular smooth muscle cell
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