Atheroprotective communication between endothelial cells and smooth muscle cells through miRNAs

Hergenreider, Eduard; Heydt, Susanne; Tréguer, Karine; Boettger, Thomas; Horrevoets, Anton J.G.; Zeiher, Andreas M.; Scheffer, Margot P.; Frangakis, Achilleas S.; Yin, Xiaoke; Mayr, Manuel; Braun, Thomas; Urbich, Carmen; Boon, Reinier A.; Dimmeler, Stefanie

doi:10.1038/ncb2441

Cited by 1,193 publications

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“…28,29 Previous studies have suggested that circulating miRNAs may act as extracellular communicators because they could be transferred to VECs and regulate atherosclerotic processes. [30][31][32] Extracellular miRNAs are especially adept at mediating gene regulation among cells in a microenvironment. 33 In this regard, subintimal inflammation and atherosclerotic lesions, which harbor complex multicellular microenvironments, may be a nexus of miRNA-based signaling.…”

Section: Discussionmentioning

confidence: 99%

Circulating MicroRNAs and the Occurrence of Acute Myocardial Infarction in Chinese Populations

Huang

Lü

et al. 2014

Circ Cardiovasc Genet

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A cute myocardial infarction (AMI) is a leading cause of morbidity and mortality worldwide. 1 Multiple conventional risk factors and serum atherosclerotic biomarkers have been established for coronary heart disease (CHD). 2 However, advances in genomics and proteomics, especially gene-expression profiling using microarray and quantitative real-time polymerase chain reaction (qPCR), have promoted the generation of many novel molecular biomarkers for AMI with potential clinical values. 3,4 Recently, microRNAs (miRNAs) have attracted extensive interest in the field of cardiovascular diseases. 5 Clinical Perspective on p 198MiRNAs are short, endogenous, noncoding RNAs that regulate gene expressions at the posttranscriptional level by binding to the 3′-untranslated regions of their target mRNAs. 6,7 MiRNAs have now emerged as key regulators of cardiac growth, vascular development, and angiogenesis. 8,9 Recent studies demonstrated that miRNAs can be detected in circulating blood and may be useful as disease biomarkers. 10,11 The levels and identities of circulating miRNAs in cardiovascular diseases have been evaluated in a series of studies. For instance, levels of some vascular and inflammation-associated miRNAs were found to be significantly lower in the plasma of 67 patients with CHD when compared with controls, 12 and the cardiac-specific miRNA, miR-208a, was only detectable in 33 patients with AMI and not Background-Circulating microRNAs ( miRNAs) are emerging as novel disease biomarkers. We aimed to explore the association between circulating miRNAs and the occurrence of acute myocardial infarction (AMI) in Chinese populations. Methods and Results-In the discovery stage, the plasma of 20 patients with AMI and 20 controls were pooled respectively and profiled by massively parallel sequencing. Seventy-seven miRNAs showed differential expression. Selected miRNAs were validated in 178 patients with AMI and 198 controls using quantitative reverse transcriptase polymerase chain reaction assays and further replicated in 150 patients with AMI and 150 controls. Results suggest that miR-320b and miR-125b levels were significantly lower in patients with AMI than in controls in both validation populations (P<0.0001). Lower levels of miR-320b and miR-125b were associated with increased occurrence of AMI (adjusted odds ratio, 4.71; 95% confidence interval, 2.96-7.48 and odds ratio, 4.27; 95% confidence interval, 2.84-6.41, respectively). Addition of the 2 miRNAs to traditional risk factors led to a significant improvement in the area under the curve from 0.822 (95% confidence interval, 0.787-0.856) to 0.871 (95% confidence interval, 0.842-0.900), with a net reclassification improvement of 20.45% (P<0.0001) and an integrated discrimination improvement of 0.16 (P<0.0001) for patients with AMI. A functional study showed that miR-320b and miR-125b could regulate the expression profiles of genes enriched in several signal transduction pathways critical for coronary heart disease in human vascular endothelial cells. Conclusions-The...

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Section: Discussionmentioning

confidence: 99%

Circulating MicroRNAs and the Occurrence of Acute Myocardial Infarction in Chinese Populations

Huang

Lü

et al. 2014

Circ Cardiovasc Genet

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“…HUVECs are both phenotypically consistent and one of the most extensively used cell culture models for study of flow‐mediated EC signaling, including numerous studies of flow responses of the arterial system17, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 (eg, atheroprone versus atheroprotective waveforms) and DNMT1‐dependent DNA methylation 17, 18. For each set of experimental comparisons, cells were used from the same cell line between subculture passages 2 to 3.…”

Section: Methodsmentioning

confidence: 99%

DNA Methyltransferase 1–Dependent DNA Hypermethylation Constrains Arteriogenesis by Augmenting Shear Stress Set Point

Heuslein

Gorick

Song

et al. 2017

JAHA

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BackgroundArteriogenesis is initiated by increased shear stress and is thought to continue until shear stress is returned to its original “set point.” However, the molecular mechanism(s) through which shear stress set point is established by endothelial cells (ECs) are largely unstudied. Here, we tested the hypothesis that DNA methyltransferase 1 (DNMT1)–dependent EC DNA methylation affects arteriogenic capacity via adjustments to shear stress set point.Methods and ResultsIn femoral artery ligation–operated C57BL/6 mice, collateral artery segments exposed to increased shear stress without a change in flow direction (ie, nonreversed flow) exhibited global DNA hypermethylation (increased 5‐methylcytosine staining intensity) and constrained arteriogenesis (30% less diameter growth) when compared with segments exposed to both an increase in shear stress and reversed‐flow direction. In vitro, ECs exposed to a flow waveform biomimetic of nonreversed collateral segments in vivo exhibited a 40% increase in DNMT1 expression, genome‐wide hypermethylation of gene promoters, and a DNMT1‐dependent 60% reduction in proarteriogenic monocyte adhesion compared with ECs exposed to a biomimetic reversed‐flow waveform. These results led us to test whether DNMT1 regulates arteriogenic capacity in vivo. In femoral artery ligation–operated mice, DNMT1 inhibition rescued arteriogenic capacity and returned shear stress back to its original set point in nonreversed collateral segments.ConclusionsIncreased shear stress without a change in flow direction initiates arteriogenic growth; however, it also elicits DNMT1‐dependent EC DNA hypermethylation. In turn, this diminishes mechanosensing, augments shear stress set point, and constrains the ultimate arteriogenic capacity of the vessel. This epigenetic effect could impact both endogenous collateralization and treatment of arterial occlusive diseases.

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“…miRNAs are resistant to nucleases due to their small size and the fact that in body fluids, they are likely protected in extracellular evesicles (EVs) or bound to protein or high‐density lipoprotein (HDL) binding partners (Brase, Wuttig, Kuner & Sultmann, 2010; Cortez et al., 2012; Reid, Kirschner & van Zandwijk, 2011; Wagner et al., 2013). This reservoir of miRNAs may transit to other cells and tissues where in some cases they influence gene regulation and may play a role in physiology and pathology (Hergenreider et al., 2012; Wei et al., 2017; Zhang et al., 2010, 2015). Earlier, we found that several circulating miRNAs are lower in abundance as humans age (Noren Hooten et al., 2010, 2013).…”

Section: Introductionmentioning

confidence: 99%

Extracellular RNA profiles with human age

Dluzen

Hooten

et al. 2018

Aging Cell

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SummaryCirculating extracellular RNAs (exRNAs) are potential biomarkers of disease. We thus hypothesized that age‐related changes in exRNAs can identify age‐related processes. We profiled both large and small RNAs in human serum to investigate changes associated with normal aging. exRNA was sequenced in 13 young (30–32 years) and 10 old (80–85 years) African American women to identify all RNA transcripts present in serum. We identified age‐related differences in several RNA biotypes, including mitochondrial transfer RNAs, mitochondrial ribosomal RNA, and unprocessed pseudogenes. Age‐related differences in unique RNA transcripts were further validated in an expanded cohort. Pathway analysis revealed that EIF2 signaling, oxidative phosphorylation, and mitochondrial dysfunction were among the top pathways shared between young and old. Protein interaction networks revealed distinct clusters of functionally‐related protein‐coding genes in both age groups. These data provide timely and relevant insight into the exRNA repertoire in serum and its change with aging.

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Atheroprotective communication between endothelial cells and smooth muscle cells through miRNAs

Cited by 1,193 publications

References 45 publications

Circulating MicroRNAs and the Occurrence of Acute Myocardial Infarction in Chinese Populations

Circulating MicroRNAs and the Occurrence of Acute Myocardial Infarction in Chinese Populations

DNA Methyltransferase 1–Dependent DNA Hypermethylation Constrains Arteriogenesis by Augmenting Shear Stress Set Point

Extracellular RNA profiles with human age

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