Oncological miR-182-3p, a Novel Smooth Muscle Cell Phenotype Modulator, Evidences From Model Rats and Patients

Abstract

Objective— Vascular smooth muscle cell (VSMC) phenotype change is a hallmark of vascular remodeling, which contributes to atherosclerotic diseases and can be regulated via microRNA-dependent mechanisms. We recently identified that asymmetrical dimethylarginine positively correlates to vascular remodeling–based diseases. We hypothesized that asymmetrical dimethylarginine induces smooth muscle cell (SMC) phenotypic change via a microRNA-dependent mechanism. Approach and Results— Microarray analysis enabled the identification of downregulation of miR-182-3p in asymmetrical dimethylarginine–treated human aortic artery SMCs. The myeloid-associated differentiation marker (MYADM) was identified as the downstream target of miR-182-3p and implicated to contribute to miR-182-3p knockdown–mediated SMC phenotype change, which was evidenced by the increased proliferation and migration and reduced expression levels of phenotype-related genes in human aortic artery SMCs through the ERK/MAP (extracellular signal-regulated kinase/mitogen-activated protein) kinase–dependent mechanism. When inhibiting MYADM in the presence of miR-182-3p inhibitor or overexpressing MYADM in the presence of pre-miR-182-3p, human aortic artery SMCs were reversed to the differentiation phenotype. In vivo, adeno-miR-182-3p markedly suppressed carotid neointimal formation by using balloon-injured rat carotid artery model, specifically via decreased MYADM expression, whereas adeno-miR-182-3p inhibitor significantly promoted neointimal formation. Atherosclerotic lesions from patients with high asymmetrical dimethylarginine plasma levels exhibited decreased miR-182-3p expression levels and elevated MYADM expression levels. Conclusions— miR-182-3p is a novel SMC phenotypic modulator by targeting MYADM .

MiR-182 regulates cell proliferation and apoptosis in laryngeal squamous cell carcinoma by targeting the CRR9

“…In recent years, miR-182 can regulate a series of physiological processes such as growth, development, and cell differentiation of biological organisms by regulating the expressions of different target genes. It also plays an oncogene in the process of malignant tumors [23,24]. The results of this study showed that the expressions of miR-182 in LSCC tissues and cells was significantly lower than that of normal adjacent normal tissues and normal cells (P<0.05).…”

Phenotype of Vascular Smooth Muscle Cells (VSMCs) Is Regulated by miR-29b by Targeting Sirtuin 1

“…The etiology of these alterations in VSMC phenotype is still unclear. Recent reports have demonstrated that miRNAs participate in the regulation of the phenotype of VSMCs [27–29]. Selective expression of miR-145 occurs in murine VSMCs, which is remarkably inhibited during the alteration in phenotype triggered by PDGF-BB in vitro as well as in balloon-damaged murine arteria carotis.…”

miR-22 Is a Novel Mediator of Vascular Smooth Muscle Cell Phenotypic Modulation and Neointima Formation

“…Of great interest to us is the growing evidence that supports a role for a novel class of gene regulators, microRNAs (miRs), in regulating VSMC differentiation from stem/progenitor cells and VSMC phenotype switching in response to vascular injury3–6. Despite the growing number of identified miRNAs that have been implicated in VSMC differentiation and phenotypic modulation in response to injury, such as miR-17, miR-15b/168, miR-219, 10, miR-34a11, 12, miR-13313, miR-143/145 cluster14–20, miR-182-3p21, miR-21422, miR-221/22223, 24, miR-63825, and miR-66326, the epigenetic regulation of VSMC phenotype switching has yet to be fully understood.…”