共 71 条
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.
引用
收藏
页数:37
相关论文