NCK Associated Protein 1 Modulated by miRNA-214 Determines Vascular Smooth Muscle Cell Migration, Proliferation, and Neointima Hyperplasia

被引:55
作者
Afzal, Tayyab Adeel [1 ]
Le Anh Luong [1 ]
Chen, Dan [1 ,4 ]
Zhang, Cheng [1 ,4 ]
Yang, Feng [1 ,5 ]
Chen, Qishan [1 ,5 ]
An, Weiwei [1 ]
Wilkes, Edmund [3 ]
Yashiro, Kenta [2 ,6 ]
Cutillas, Pedro R. [3 ]
Zhang, Li [5 ]
Xiao, Qingzhong [1 ]
机构
[1] Queen Mary Univ London, Barts & London Sch Med & Dent, Ctr Clin Pharmacol, William Harvey Res Inst, London, England
[2] Queen Mary Univ London, Barts & London Sch Med & Dent, Translat Med & Therapeut, William Harvey Res Inst, London, England
[3] Queen Mary Univ London, Barts & London Sch Med & Dent, Barts Canc Inst, Ctr Haematooncol, London, England
[4] Chongqing Med Univ, Affiliated Hosp 1, Dept Cardiothorac Surg, Chongqing, Peoples R China
[5] Zhejiang Univ, Affiliated Hosp 1, Sch Med, Dept Cardiol, Hangzhou, Zhejiang, Peoples R China
[6] Osaka Univ, Grad Sch Med, Dept Cardiovasc Surg Cardiac Regenerat & Therapeu, Yamada Oka 2-2, Suita, Osaka 5650871, Japan
来源
JOURNAL OF THE AMERICAN HEART ASSOCIATION | 2016年 / 5卷 / 12期
基金
中国国家自然科学基金;
关键词
cell migration; cell proliferation; microRNA; miRNA-214; NCK-associated protein 1; neointimal hyperplasia; vascular biology; vascular disease; vascular smooth muscle; IN-VIVO; MATRIX METALLOPROTEINASE-8; STEM-CELLS; ENDOTHELIAL-CELLS; CARDIAC-HYPERTROPHY; PHENOTYPIC SWITCH; LESION FORMATION; HEART-FAILURE; MICRORNA-214; DIFFERENTIATION;
D O I
10.1161/JAHA.116.004629
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
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页数:37
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