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 was...
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Wiley
2016-12-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
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| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.116.004629 |
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| author | Tayyab Adeel Afzal Le Anh Luong Dan Chen Cheng Zhang Feng Yang Qishan Chen Weiwei An Edmund Wilkes Kenta Yashiro Pedro R. Cutillas Li Zhang Qingzhong Xiao |
| author_facet | Tayyab Adeel Afzal Le Anh Luong Dan Chen Cheng Zhang Feng Yang Qishan Chen Weiwei An Edmund Wilkes Kenta Yashiro Pedro R. Cutillas Li Zhang Qingzhong Xiao |
| author_sort | Tayyab Adeel Afzal |
| collection | DOAJ |
| 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 | Article |
| id | doaj-art-c097f5e8833a422f8ca7136bf9b42aa0 |
| institution | Matheson Library |
| issn | 2047-9980 |
| language | English |
| publishDate | 2016-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj-art-c097f5e8833a422f8ca7136bf9b42aa02025-07-04T05:15:20ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802016-12-0151210.1161/JAHA.116.004629NCK Associated Protein 1 Modulated by miRNA‐214 Determines Vascular Smooth Muscle Cell Migration, Proliferation, and Neointima HyperplasiaTayyab Adeel Afzal0Le Anh Luong1Dan Chen2Cheng Zhang3Feng Yang4Qishan Chen5Weiwei An6Edmund Wilkes7Kenta Yashiro8Pedro R. Cutillas9Li Zhang10Qingzhong Xiao11Centre for Clinical Pharmacology William Harvey Research Institute Barts and The London School of Medicine and Dentistry Queen Mary University of London United KingdomCentre for Clinical Pharmacology William Harvey Research Institute Barts and The London School of Medicine and Dentistry Queen Mary University of London United KingdomCentre for Clinical Pharmacology William Harvey Research Institute Barts and The London School of Medicine and Dentistry Queen Mary University of London United KingdomCentre for Clinical Pharmacology William Harvey Research Institute Barts and The London School of Medicine and Dentistry Queen Mary University of London United KingdomCentre for Clinical Pharmacology William Harvey Research Institute Barts and The London School of Medicine and Dentistry Queen Mary University of London United KingdomCentre for Clinical Pharmacology William Harvey Research Institute Barts and The London School of Medicine and Dentistry Queen Mary University of London United KingdomCentre for Clinical Pharmacology William Harvey Research Institute Barts and The London School of Medicine and Dentistry Queen Mary University of London United KingdomCentre for Haemato‐Oncology Barts Cancer Institute Barts and The London School of Medicine and Dentistry Queen Mary University of London United KingdomTranslational Medicine & Therapeutics William Harvey Research Institute Barts and The London School of Medicine and Dentistry Queen Mary University of London United KingdomCentre for Haemato‐Oncology Barts Cancer Institute Barts and The London School of Medicine and Dentistry Queen Mary University of London United KingdomDepartment of Cardiology The First Affiliated Hospital School of Medicine Zhejiang University Hangzhou Zhejiang ChinaCentre for Clinical Pharmacology William Harvey Research Institute Barts and The London School of Medicine and Dentistry Queen Mary University of London United KingdomBackground 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.https://www.ahajournals.org/doi/10.1161/JAHA.116.004629cell migrationcell proliferationmicroRNAmiRNA‐214NCK‐associated protein 1neointimal hyperplasia |
| spellingShingle | Tayyab Adeel Afzal Le Anh Luong Dan Chen Cheng Zhang Feng Yang Qishan Chen Weiwei An Edmund Wilkes Kenta Yashiro Pedro R. Cutillas Li Zhang Qingzhong Xiao NCK Associated Protein 1 Modulated by miRNA‐214 Determines Vascular Smooth Muscle Cell Migration, Proliferation, and Neointima Hyperplasia Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease cell migration cell proliferation microRNA miRNA‐214 NCK‐associated protein 1 neointimal 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 | cell migration cell proliferation microRNA miRNA‐214 NCK‐associated protein 1 neointimal hyperplasia |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.116.004629 |
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