Cargando…
NCK Associated Protein 1 Modulated by miRNA‐214 Determines Vascular Smooth Muscle Cell Migration, Proliferation, and Neointima Hyperplasia
BACKGROUND: MicroRNA miR‐214 has been implicated in many biological cellular functions, but the impact of miR‐214 and its target genes on vascular smooth muscle cell (VSMC) proliferation, migration, and neointima smooth muscle cell hyperplasia is unknown. METHODS AND RESULTS: Expression of miR‐214 w...
Autores principales: | , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2016
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5210428/ https://www.ncbi.nlm.nih.gov/pubmed/27927633 http://dx.doi.org/10.1161/JAHA.116.004629 |
_version_ | 1782490885247729664 |
---|---|
author | Afzal, Tayyab Adeel Luong, Le Anh Chen, Dan Zhang, Cheng Yang, Feng Chen, Qishan An, Weiwei Wilkes, Edmund Yashiro, Kenta Cutillas, Pedro R. Zhang, Li Xiao, Qingzhong |
author_facet | Afzal, Tayyab Adeel Luong, Le Anh Chen, Dan Zhang, Cheng Yang, Feng Chen, Qishan An, Weiwei Wilkes, Edmund Yashiro, Kenta Cutillas, Pedro R. Zhang, Li Xiao, Qingzhong |
author_sort | Afzal, Tayyab Adeel |
collection | PubMed |
description | BACKGROUND: MicroRNA miR‐214 has been implicated in many biological cellular functions, but the impact of miR‐214 and its target genes on vascular smooth muscle cell (VSMC) proliferation, migration, and neointima smooth muscle cell hyperplasia is unknown. METHODS AND RESULTS: Expression of miR‐214 was closely regulated by different pathogenic stimuli in VSMCs through a transcriptional mechanism and decreased in response to vascular injury. Overexpression of miR‐214 in serum‐starved VSMCs significantly decreased VSMC proliferation and migration, whereas knockdown of miR‐214 dramatically increased VSMC proliferation and migration. Gene and protein biochemical assays, including proteomic analyses, showed that NCK associated protein 1 (NCKAP1)—a major component of the WAVE complex that regulates lamellipodia formation and cell motility—was negatively regulated by miR‐214 in VSMCs. Luciferase assays showed that miR‐214 substantially repressed wild‐type but not the miR‐214 binding site mutated version of NCKAP1 3′ untranslated region luciferase activity in VSMCs. This result confirmed that NCKAP1 is the functional target of miR‐214 in VSMCs. NCKAP1 knockdown in VSMCs recapitulates the inhibitory effects of miR‐214 overexpression on actin polymerization, cell migration, and proliferation. Data from cotransfection experiments also revealed that inhibition of NCKAP1 is required for miR‐214–mediated lamellipodia formation, cell motility, and growth. Importantly, locally enforced expression of miR‐214 in the injured vessels significantly reduced NCKAP1 expression levels, inhibited VSMC proliferation, and prevented neointima smooth muscle cell hyperplasia after injury. CONCLUSIONS: We uncovered an important role of miR‐214 and its target gene NCKAP1 in modulating VSMC functions and neointima hyperplasia. Our findings suggest that miR‐214 represents a potential therapeutic target for vascular diseases. |
format | Online Article Text |
id | pubmed-5210428 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-52104282017-01-05 NCK Associated Protein 1 Modulated by miRNA‐214 Determines Vascular Smooth Muscle Cell Migration, Proliferation, and Neointima Hyperplasia Afzal, Tayyab Adeel Luong, Le Anh Chen, Dan Zhang, Cheng Yang, Feng Chen, Qishan An, Weiwei Wilkes, Edmund Yashiro, Kenta Cutillas, Pedro R. Zhang, Li Xiao, Qingzhong J Am Heart Assoc Original Research BACKGROUND: MicroRNA miR‐214 has been implicated in many biological cellular functions, but the impact of miR‐214 and its target genes on vascular smooth muscle cell (VSMC) proliferation, migration, and neointima smooth muscle cell hyperplasia is unknown. METHODS AND RESULTS: Expression of miR‐214 was closely regulated by different pathogenic stimuli in VSMCs through a transcriptional mechanism and decreased in response to vascular injury. Overexpression of miR‐214 in serum‐starved VSMCs significantly decreased VSMC proliferation and migration, whereas knockdown of miR‐214 dramatically increased VSMC proliferation and migration. Gene and protein biochemical assays, including proteomic analyses, showed that NCK associated protein 1 (NCKAP1)—a major component of the WAVE complex that regulates lamellipodia formation and cell motility—was negatively regulated by miR‐214 in VSMCs. Luciferase assays showed that miR‐214 substantially repressed wild‐type but not the miR‐214 binding site mutated version of NCKAP1 3′ untranslated region luciferase activity in VSMCs. This result confirmed that NCKAP1 is the functional target of miR‐214 in VSMCs. NCKAP1 knockdown in VSMCs recapitulates the inhibitory effects of miR‐214 overexpression on actin polymerization, cell migration, and proliferation. Data from cotransfection experiments also revealed that inhibition of NCKAP1 is required for miR‐214–mediated lamellipodia formation, cell motility, and growth. Importantly, locally enforced expression of miR‐214 in the injured vessels significantly reduced NCKAP1 expression levels, inhibited VSMC proliferation, and prevented neointima smooth muscle cell hyperplasia after injury. CONCLUSIONS: We uncovered an important role of miR‐214 and its target gene NCKAP1 in modulating VSMC functions and neointima hyperplasia. Our findings suggest that miR‐214 represents a potential therapeutic target for vascular diseases. John Wiley and Sons Inc. 2016-12-07 /pmc/articles/PMC5210428/ /pubmed/27927633 http://dx.doi.org/10.1161/JAHA.116.004629 Text en © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial (http://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | Original Research Afzal, Tayyab Adeel Luong, Le Anh Chen, Dan Zhang, Cheng Yang, Feng Chen, Qishan An, Weiwei Wilkes, Edmund Yashiro, Kenta Cutillas, Pedro R. Zhang, Li Xiao, Qingzhong NCK Associated Protein 1 Modulated by miRNA‐214 Determines Vascular Smooth Muscle Cell Migration, Proliferation, and Neointima Hyperplasia |
title | NCK Associated Protein 1 Modulated by miRNA‐214 Determines Vascular Smooth Muscle Cell Migration, Proliferation, and Neointima Hyperplasia |
title_full | NCK Associated Protein 1 Modulated by miRNA‐214 Determines Vascular Smooth Muscle Cell Migration, Proliferation, and Neointima Hyperplasia |
title_fullStr | NCK Associated Protein 1 Modulated by miRNA‐214 Determines Vascular Smooth Muscle Cell Migration, Proliferation, and Neointima Hyperplasia |
title_full_unstemmed | NCK Associated Protein 1 Modulated by miRNA‐214 Determines Vascular Smooth Muscle Cell Migration, Proliferation, and Neointima Hyperplasia |
title_short | NCK Associated Protein 1 Modulated by miRNA‐214 Determines Vascular Smooth Muscle Cell Migration, Proliferation, and Neointima Hyperplasia |
title_sort | nck associated protein 1 modulated by mirna‐214 determines vascular smooth muscle cell migration, proliferation, and neointima hyperplasia |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5210428/ https://www.ncbi.nlm.nih.gov/pubmed/27927633 http://dx.doi.org/10.1161/JAHA.116.004629 |
work_keys_str_mv | AT afzaltayyabadeel nckassociatedprotein1modulatedbymirna214determinesvascularsmoothmusclecellmigrationproliferationandneointimahyperplasia AT luongleanh nckassociatedprotein1modulatedbymirna214determinesvascularsmoothmusclecellmigrationproliferationandneointimahyperplasia AT chendan nckassociatedprotein1modulatedbymirna214determinesvascularsmoothmusclecellmigrationproliferationandneointimahyperplasia AT zhangcheng nckassociatedprotein1modulatedbymirna214determinesvascularsmoothmusclecellmigrationproliferationandneointimahyperplasia AT yangfeng nckassociatedprotein1modulatedbymirna214determinesvascularsmoothmusclecellmigrationproliferationandneointimahyperplasia AT chenqishan nckassociatedprotein1modulatedbymirna214determinesvascularsmoothmusclecellmigrationproliferationandneointimahyperplasia AT anweiwei nckassociatedprotein1modulatedbymirna214determinesvascularsmoothmusclecellmigrationproliferationandneointimahyperplasia AT wilkesedmund nckassociatedprotein1modulatedbymirna214determinesvascularsmoothmusclecellmigrationproliferationandneointimahyperplasia AT yashirokenta nckassociatedprotein1modulatedbymirna214determinesvascularsmoothmusclecellmigrationproliferationandneointimahyperplasia AT cutillaspedror nckassociatedprotein1modulatedbymirna214determinesvascularsmoothmusclecellmigrationproliferationandneointimahyperplasia AT zhangli nckassociatedprotein1modulatedbymirna214determinesvascularsmoothmusclecellmigrationproliferationandneointimahyperplasia AT xiaoqingzhong nckassociatedprotein1modulatedbymirna214determinesvascularsmoothmusclecellmigrationproliferationandneointimahyperplasia |