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NCK associated protein 1 modulated by miRNA-214 determines vascular smooth muscle cell migration,proliferation,and neointima hyperplasia
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نویسنده
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afzal t.a. ,luong l.a. ,chen d. ,zhang c. ,yang f. ,chen q. ,an w. ,wilkes e. ,yashiro k. ,cutillas p.r. ,zhang l. ,xiao q.
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منبع
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journal of the american heart association - 2016 - دوره : 5 - شماره : 12
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چکیده
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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 30 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. © 2016 the authors.
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کلیدواژه
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Cell migration; Cell proliferation; MicroRNA; MiRNA-214; NCK-associated protein 1; Neointimal hyperplasia; Vascular biology; Vascular disease; Vascular smooth muscle
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آدرس
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centre for clinical pharmacology,william harvey research institute,barts and the london school of medicine and dentistry,queen mary university of london, United Kingdom, centre for clinical pharmacology,william harvey research institute,barts and the london school of medicine and dentistry,queen mary university of london, United Kingdom, centre for clinical pharmacology,william harvey research institute,barts and the london school of medicine and dentistry,queen mary university of london,united kingdom,department of cardiothoracic surgery,the first affiliated hospital of chongqing medical university,chongqing, China, centre for clinical pharmacology,william harvey research institute,barts and the london school of medicine and dentistry,queen mary university of london,united kingdom,department of cardiothoracic surgery,the first affiliated hospital of chongqing medical university,chongqing, China, centre for clinical pharmacology,william harvey research institute,barts and the london school of medicine and dentistry,queen mary university of london,united kingdom,department of cardiology,the first affiliated hospital,school of medicine,zhejiang university,hangzhou,zhejiang, China, centre for clinical pharmacology,william harvey research institute,barts and the london school of medicine and dentistry,queen mary university of london,united kingdom,department of cardiology,the first affiliated hospital,school of medicine,zhejiang university,hangzhou,zhejiang, China, centre for clinical pharmacology,william harvey research institute,barts and the london school of medicine and dentistry,queen mary university of london, United Kingdom, centre for haemato-oncology,barts cancer institute,barts and the london school of medicine and dentistry,queen mary university of london, United Kingdom, translational medicine and therapeutics,william harvey research institute,barts and the london school of medicine and dentistry,queen mary university of london,united kingdom,department of cardiovascular surgery,cardiac regeneration and therapeutics,osaka university graduate school of medicine,yamada-oka 2-2,suita,osaka,565-0871, Japan, centre for haemato-oncology,barts cancer institute,barts and the london school of medicine and dentistry,queen mary university of london, United Kingdom, department of cardiology,the first affiliated hospital,school of medicine,zhejiang university,hangzhou,zhejiang, China, centre for clinical pharmacology,william harvey research institute,barts and the london school of medicine and dentistry,queen mary university of london, United Kingdom
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Authors
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