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

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

doi:10.1161/JAHA.116.004629

Back

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

Journal article

Open access

Peer reviewed

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

Tayyab Adeel Afzal, Le Anh Luong, Dan Chen, Cheng Zhang, Feng Yang, Qishan Chen, Weiwei An, Edmund Wilkes, Kenta Yashiro, Pedro R Cutillas, …

Journal of the American Heart Association, Vol.5(12), p.n/a

12/07/2016

DOI: 10.1161/JAHA.116.004629

PMCID: PMC5210428

PMID: 27927633

Files and links (1)

url

https://doi.org/10.1161/JAHA.116.004629View

Published (Version of record) Open Access

Abstract

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. 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. 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.

Proteomics

Angiogenesis Inducing Agents - pharmacology

Animals

Becaplermin

Binding Sites - genetics

Cell Line

Cell Movement - physiology

Cell Proliferation - physiology

Down-Regulation

Femoral Artery - surgery

Gene Knockdown Techniques

Hyperplasia - pathology

Membrane Proteins - antagonists & inhibitors

Membrane Proteins - genetics

Membrane Proteins - physiology

Mice

Mice, Inbred C57BL

MicroRNAs - metabolism

MicroRNAs - physiology

Muscle, Smooth, Vascular - physiology

Mutation - genetics

Myocytes, Smooth Muscle

Neointima - pathology

Proto-Oncogene Proteins c-sis - pharmacology

RNA, Small Interfering - physiology

Twist-Related Protein 1 - antagonists & inhibitors

Details

Title: Subtitle: NCK Associated Protein 1 Modulated by miRNA-214 Determines Vascular Smooth Muscle Cell Migration, Proliferation, and Neointima Hyperplasia
Creators: Tayyab Adeel Afzal - University of Iowa, Internal Medicine
Le Anh Luong - Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom
Dan Chen - Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
Cheng Zhang - Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
Feng Yang - Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
Qishan Chen - Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
Weiwei An - Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom
Edmund Wilkes - Centre for Haemato-Oncology, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom
Kenta Yashiro - Translational Medicine & Therapeutics, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom
Pedro R Cutillas - Centre for Haemato-Oncology, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom
Li Zhang - Zhejiang University
Qingzhong Xiao - University of Iowa, Health and Human Physiology
Resource Type: Journal article
Publication Details: Journal of the American Heart Association, Vol.5(12), p.n/a
DOI: 10.1161/JAHA.116.004629
PMID: 27927633
PMCID: PMC5210428
ISSN: 2047-9980
eISSN: 2047-9980
Grant note: PG/15/11/31279 / British Heart Foundation PG/15/86/31723 / British Heart Foundation PG/13/45/30326 / British Heart Foundation PG/16/1/31892 / British Heart Foundation FS/09/044/28007 / British Heart Foundation PG/11/40/28891 / British Heart Foundation
Language: English
Date published: 12/07/2016
Academic Unit: Internal Medicine
Record Identifier: 9984130695102771

Metrics

26 Record Views

50 Times Cited - Web of Science

See more details