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miR-424/322 regulates vascular smooth muscle cell phenotype and neointimal formation in the rat.
- Source :
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Cardiovascular research [Cardiovasc Res] 2013 Jun 01; Vol. 98 (3), pp. 458-68. Date of Electronic Publication: 2013 Feb 26. - Publication Year :
- 2013
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Abstract
- Aims: Our aim was to identify new microRNAs (miRNAs) implicated in pathological vascular smooth muscle cells (VSMCs) proliferation and characterize their mechanism of action.<br />Methods and Results: MicroRNAs microarray and qRT-PCR results lead us to focus on miR-424 or its rat ortholog miR-322 (miR-424/322). In vitro mir-424/322 level was decreased shortly after the induction of proliferation and increased in a time-dependent manner later on. In vivo its expression increased in the rat carotid artery from Day 4 up to Day 30 after injury. miR-424/322 overexpression in vitro inhibited proliferation and migration without affecting apoptosis and prevented VSMC dedifferentiation. Furthermore, miR-424/322 overexpression resulted in decreased expression of its predicted targets: cyclin D1 and Ca(2+)-regulating proteins calumenin and stromal-interacting molecule 1 (STIM1). Using reporter luciferase assays, we confirmed that cyclin D1 and calumenin mRNAs were direct targets of miR-322, whereas miR-322 effect on STIM1 was indirect. Nevertheless, consistent with the decreased STIM1 level, the store-operated Ca(2+) entry was reduced. We hypothesized that miR-424/322 could be a negative regulator of proliferation overridden in pathological situations. Thus, we overexpressed miR-424/322 in injured rat carotid arteries using an adenovirus, and demonstrated a protective effect against restenosis.<br />Conclusion: Our results demonstrate that miR-424/322 is up-regulated after vascular injury. This is likely an adaptive response to counteract proliferation, although this mechanism is overwhelmed in pathological situations such as injury-induced restenosis.
- Subjects :
- Animals
Apoptosis
Calcium metabolism
Calcium-Binding Proteins metabolism
Carotid Artery Injuries genetics
Carotid Artery Injuries pathology
Carotid Artery Injuries prevention & control
Carotid Artery, External metabolism
Carotid Artery, External pathology
Cell Dedifferentiation
Cell Movement
Cell Proliferation
Cells, Cultured
Cyclin D1 metabolism
Disease Models, Animal
Humans
Male
Membrane Glycoproteins metabolism
Muscle, Smooth, Vascular pathology
Myocytes, Smooth Muscle pathology
Phenotype
Rats
Rats, Wistar
Signal Transduction
Stromal Interaction Molecule 1
Time Factors
Transfection
Up-Regulation
Carotid Artery Injuries metabolism
MicroRNAs metabolism
Muscle, Smooth, Vascular metabolism
Myocytes, Smooth Muscle metabolism
Neointima
Subjects
Details
- Language :
- English
- ISSN :
- 1755-3245
- Volume :
- 98
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Cardiovascular research
- Publication Type :
- Academic Journal
- Accession number :
- 23447642
- Full Text :
- https://doi.org/10.1093/cvr/cvt045