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1.
J Mol Cell Cardiol ; 104: 43-52, 2017 03.
Article in English | MEDLINE | ID: mdl-28143713

ABSTRACT

BACKGROUND: Vascular smooth muscle cell (VSMC) proliferation is of importance in the pathogenesis of vascular diseases such as restenosis or atherosclerosis. Endothelial microparticles (EMPs) regulate function and phenotype of target endothelial cells (ECs), but their influence on VSMC biology is unknown. We aim to investigate the role of EMPs in the regulation of vascular smooth muscle cell (VSMC) proliferation and vascular remodeling. METHODS AND RESULTS: Systemic treatment of mice with EMPs after vascular injury reduced neointima formation in vivo. In vitro, EMP uptake in VSMCs diminished VSMC proliferation and migration, both pivotal steps in neointima formation. To explore the underlying mechanisms, Taqman microRNA-array was performed and miR-126-3p was identified as the predominantly expressed miR in EMPs. Confocal microscopy revealed an EMP-mediated miR-126 transfer into recipient VSMCs. Expression of miR-126 target protein LRP6, regulating VSMC proliferation, was reduced in VSMCs after EMP treatment. Importantly, genetic regulation of miR-126 in EMPs showed a miR-126-dependent inhibition of LRP6 expression, VSMC proliferation and neointima formation in vitro and in vivo, suggesting a crucial role of miR-126 in EMP-mediated neointima formation reduction. Finally, analysis of miR-126 expression in circulating MPs in 176 patients with coronary artery disease revealed a reduced PCI rate in patients with high miR-126 expression level, supporting a central role for MP-incorporated miR-126 in vascular remodelling. CONCLUSION: EMPs reduce VSMC proliferation, migration and subsequent neointima formation by delivering functional miR-126 into recipient VSMCs.


Subject(s)
Cell-Derived Microparticles/metabolism , Endothelial Cells/metabolism , Low Density Lipoprotein Receptor-Related Protein-6/genetics , MicroRNAs/genetics , Muscle, Smooth, Vascular/metabolism , Myocytes, Smooth Muscle/metabolism , Neointima/metabolism , Aged , Animals , Atherosclerosis/genetics , Atherosclerosis/metabolism , Atherosclerosis/pathology , Biological Transport , Cell Proliferation , Disease Models, Animal , Female , Gene Expression Regulation , Humans , Immunohistochemistry , Low Density Lipoprotein Receptor-Related Protein-6/metabolism , Male , Mice , Mice, Knockout , MicroRNAs/metabolism , Middle Aged , Neointima/pathology , RNA Interference
2.
J Am Heart Assoc ; 3(6): e001249, 2014 Oct 27.
Article in English | MEDLINE | ID: mdl-25349183

ABSTRACT

BACKGROUND: Circulating microRNAs (miRNAs) are differentially regulated and selectively packaged in microvesicles (MVs). We evaluated whether circulating vascular and endothelial miRNAs in patients with stable coronary artery disease have prognostic value for the occurrence of cardiovascular (CV) events. METHODS AND RESULTS: Ten miRNAs involved in the regulation of vascular performance-miR-126, miR-222, miR-let7d, miR-21, miR-20a, miR-27a, miR-92a, miR-17, miR-130, and miR-199a-were quantified in plasma and circulating MVs by reverse transcription polymerase chain reaction in 181 patients with stable coronary artery disease. The median duration of follow-up for major adverse CV event-free survival was 6.1 years (range: 6.0-6.4 years). Events occurred in 55 patients (31.3%). There was no significant association between CV events and plasma level of the selected miRNAs. In contrast, increased expression of miR-126 and miR-199a in circulating MVs was significantly associated with a lower major adverse CV event rate. In univariate analysis, above-median levels of miR-126 in circulating MVs were predictors of major adverse CV event-free survival (hazard ratio: 0.485 [95% CIAUTHOR: Is 95% CI correct?: 0.278 to 0.846]; P=0.007) and percutaneous coronary interventions (hazard ratio: 0.458 [95% CI: 0.222 to 0.945]; P=0.03). Likewise, an increased level of miR-199a in circulating MVs was associated with a reduced risk of major adverse CV events (hazard ratio: 0.518 [95% CI: 0.299 to 0.898]; P=0.01) and revascularization (hazard ratio: 0.439 [95% CI: 0.232 to 0.832]; P=0.01) in univariate analysis. miRNA expression analysis in plasma compartments revealed that miR-126 and miR-199a are present mainly in circulating MVs. MV-sorting experiments showed that endothelial cells and platelets were found to be the major cell sources of MVs containing miR-126 and miR-199a, respectively. CONCLUSION: MVs containing miR-126 and miR-199a but not freely circulating miRNA expression predict the occurrence of CV events in patients with stable coronary artery disease.


Subject(s)
Cell-Derived Microparticles/metabolism , Coronary Artery Disease/blood , Coronary Artery Disease/genetics , Endothelial Cells/metabolism , MicroRNAs/blood , MicroRNAs/genetics , Aged , Coronary Angiography , Coronary Artery Disease/diagnosis , Coronary Artery Disease/mortality , Coronary Artery Disease/therapy , Disease Progression , Disease-Free Survival , Female , Genetic Markers , Genetic Predisposition to Disease , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Phenotype , Prospective Studies , Protective Factors , Risk Assessment , Risk Factors , Time Factors
3.
Circulation ; 128(18): 2026-38, 2013 Oct 29.
Article in English | MEDLINE | ID: mdl-24014835

ABSTRACT

BACKGROUND: Repair of the endothelium after vascular injury is crucial for preserving endothelial integrity and preventing the development of vascular disease. The underlying mechanisms of endothelial cell repair are largely unknown. We sought to investigate whether endothelial microparticles (EMPs), released from apoptotic endothelial cells (ECs), influence EC repair. METHODS AND RESULTS: Systemic treatment of mice with EMPs after electric denudation of the endothelium accelerated reendothelialization in vivo. In vitro experiments revealed that EMP uptake in ECs promotes EC migration and proliferation, both critical steps in endothelial repair. To dissect the underlying mechanisms, Taqman microRNA array was performed, and microRNA (miR)-126 was identified as the predominantly expressed miR in EMPs. The following experiments demonstrated that miR-126 was transported into recipient human coronary artery endothelial cells by EMPs and functionally regulated the target protein sprouty-related, EVH1 domain-containing protein 1 (SPRED1). Knockdown of miR-126 in EMPs abrogated EMP-mediated effects on human coronary artery endothelial cell migration and proliferation in vitro and reendothelialization in vivo. Interestingly, after simulating diabetic conditions, EMPs derived from glucose-treated ECs contained significantly lower amounts of miR-126 and showed reduced endothelial repair capacity in vitro and in vivo. Finally, expression analysis of miR-126 in circulating microparticles from 176 patients with stable coronary artery disease with and without diabetes mellitus revealed a significantly reduced miR-126 expression in circulating microparticles from diabetic patients. CONCLUSIONS: Endothelial microparticles promote vascular endothelial repair by delivering functional miR-126 into recipient cells. In pathological hyperglycemic conditions, EMP-mediated miR-126-induced EC repair is altered.


Subject(s)
Cell-Derived Microparticles/physiology , Coronary Vessels/physiology , Endothelial Cells/physiology , Intracellular Signaling Peptides and Proteins/metabolism , Membrane Proteins/metabolism , MicroRNAs/metabolism , Repressor Proteins/metabolism , Adaptor Proteins, Signal Transducing , Animals , Carotid Artery Injuries/metabolism , Carotid Artery Injuries/pathology , Carotid Artery Injuries/physiopathology , Cell Movement/physiology , Cell Proliferation , Cell-Derived Microparticles/pathology , Cells, Cultured , Coronary Artery Disease/metabolism , Coronary Artery Disease/pathology , Coronary Artery Disease/physiopathology , Coronary Vessels/injuries , Coronary Vessels/pathology , Endothelial Cells/pathology , Glucose/toxicity , Humans , Hyperglycemia/metabolism , Hyperglycemia/pathology , Mice, Inbred C57BL , Wound Healing/physiology
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