Downregulation of MicroRNA-126 Augments DNA Damage Response in Cigarette Smokers and Patients with Chronic Obstructive Pulmonary Disease

Paschalaki, Koralia; Zampetaki, Anna; Baker, Jonathan; Birrell, Mark A.; Starke, Richard; Belvisi, Maria G.; Donnelly, Louise E.; Mayr, Manuel; Randi, Anna M.; Barnes, Peter J.

doi:10.1164/rccm.201706-1304le

Cited by 37 publications

(26 citation statements)

References 10 publications

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“…Further studies demonstrated microRNA dysregulation in ECFC from COPD, affecting the miR-126-3p, a critical microRNA in vascular development, endothelial homeostasis and inflammation ( 53 ). We found that miR-126-3p is downregulated in ECFC from smokers and COPD patients and promotes an augmented DNA damage response through activation of ATM, contributing to endothelial senescence and dysfunction in these groups ( 54 ).…”

Section: Ecfc For the Investigation Of Endothelial Cell Biology In DImentioning

confidence: 99%

Recent Advances in Endothelial Colony Forming Cells Toward Their Use in Clinical Translation

Paschalaki

Randi

2018

Front. Med.

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The term “Endothelial progenitor cell” (EPC) has been used to describe multiple cell populations that express endothelial surface makers and promote vascularisation. However, the only population that has all the characteristics of a real “EPC” is the Endothelial Colony Forming Cells (ECFC). ECFC possess clonal proliferative potential, display endothelial and not myeloid cell surface markers, and exhibit pronounced postnatal vascularisation ability in vivo. ECFC have been used to investigate endothelial molecular dysfunction in several diseases, as they give access to endothelial cells from patients in a non-invasive way. ECFC also represent a promising tool for revascularization of damaged tissue. Here we review the translational applications of ECFC research. We discuss studies which have used ECFC to investigate molecular endothelial abnormalities in several diseases and review the evidence supporting the use of ECFC for autologous cell therapy, gene therapy and tissue regeneration. Finally, we discuss ways to improve the therapeutic efficacy of ECFC in clinical applications, as well as the challenges that must be overcome to use ECFC in clinical trials for regenerative approaches.

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Section: Ecfc For the Investigation Of Endothelial Cell Biology In DImentioning

confidence: 99%

Recent Advances in Endothelial Colony Forming Cells Toward Their Use in Clinical Translation

Paschalaki

Randi

2018

Front. Med.

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“…indicated that deregulation of miR-126 is associated with activation of ATM kinase. [ 50 ] They showed that the levels of miR-126 were downregulated in blood outgrowth endothelial cells from smokers and COPD patients compared with nonsmoker subjects. These results suggested that downregulation of miR-126 via targeting ATM could promote tissue aging and dysfunction in smoker and COPD subjects.…”

Section: Micro-rna As Diagnostic and Therapeutic Biomarkers In Chronimentioning

confidence: 99%

Chronic obstructive pulmonary disease: MicroRNAs and exosomes as new diagnostic and therapeutic biomarkers

et al. 2018

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Chronic obstructive pulmonary disease (COPD) is known as a progressive lung disease and the fourth leading cause of death worldwide. Despite valuable efforts, there is still no accurate diagnostic and prognostic tool for COPD. Hence, it seems that finding new biomarkers could contribute to provide better therapeutic platforms for COPD patients. Among various biomarkers, microRNAs (miRNAs) have emerged as new biomarkers for the prognosis and diagnosis of patients with COPD. It has been shown that deregulation of miRNAs targeting a variety of cellular and molecular pathways such as Notch, Wnt, hypoxia-inducible factor-1α, transforming growth factor, Kras, and Smad could be involved in COPD pathogenesis. Multiple lines of evidence have indicated that extracellular vesicles such as exosomes could carry a variety of cargos (i.e., mRNAs, miRNAs, and proteins) which transfer various cellular and molecular signals to recipient cells. Here, we summarized various miRNAs which could be applied as diagnostic and prognostic biomarkers in the treatment of patients with COPD. Moreover, we highlighted the role of extracellular vesicles containing miRNAs as diagnostic and prognostic biomarkers in COPD patients.

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“…An increase in epithelial expression of BRCA1 is a novel finding in COPD and suggests that decreased miR-24-3p does not simply increase apoptosis priming but priming of the whole DDR. This notion that regulatory elements prime the DDR in COPD is supported by a recent letter by Paschalaki et al who identified that miR-126-3p is decreased in COPD and miR-126-3p suppresses the DDR protein ataxia telangiectasia mutated (ATM) (8). Future studies will be necessary to determine the role of specific DDR elements, such as BRCA1, in COPD pathogenesis.…”

Section: Discussionmentioning

confidence: 81%

“…DNA damage is a well-described consequence of CS exposure and growing evidence from genetic association studies and animal models of disease have suggested an important role for cellular responses to DNA damage in the pathobiology of COPD (4)(5)(6)(7)(8). DNA damage occurs in all cells from endogenous (e.g.…”

Section: Introductionmentioning

confidence: 99%

Decreased miR-24-3p potentiates DNA damage responses and increases susceptibility to COPD

Nouws

Wan

Finnemore

et al. 2020

Preprint

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COI: EF is currently employed by Rubius Therapeutics; VN is currently employed by Akoya Bioscience; RB is cofounder and consultant for Cybrexa Therapeutics; MS and PJL are co-inventors on a pending patent describing the therapeutic utility of MIF020 in lung disease; NK reports personal fees from Biogen Idec, Boehringer Ingelheim, Third Rock, Miragen, Pliant, Samumed, NuMedii, Indaloo, Theravance, LifeMax, Optikira, Three Lake Partners and has filed patents related to the use of thyroid hormone as an antifibrotic agent and novel biomarkers in pulmonary fibrosis. ABSTRACTActivation of the DNA damage response (DDR) due to chronic exposure to cigarette smoke (CS) is implicated in the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD). However, not all smokers develop COPD and the pathologic consequences of CS exposure are heterogenous. Cellular mechanisms that regulate the DDR and contribute to disease progression in susceptible individuals are poorly understood. Because microRNAs are well known regulators of the DDR, we evaluated microRNA expression arrays performed on lung samples from 172 subjects with and without COPD. We identified miR-24-3p as the microRNA best correlated with radiographic emphysema (ρ=-0.353, P=1.3e-04) and validated this finding in multiple cohorts.In a CS-exposure mouse model, miR-24-3p inhibition increased emphysema severity. In human airway epithelial cells, miR-24-3p suppressed apoptosis through the BH3-only protein BIM and suppressed homologydirected DNA repair and the DNA repair protein BRCA1. Finally, we found BIM and BRCA1 were increased in COPD lung tissue and inversely correlated with miR-24-3p expression. We concluded that decreased miR-24-3p expression increases COPD susceptibility and potentiates the DDR through BIM and BRCA1.

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Downregulation of MicroRNA-126 Augments DNA Damage Response in Cigarette Smokers and Patients with Chronic Obstructive Pulmonary Disease

Cited by 37 publications

References 10 publications

Recent Advances in Endothelial Colony Forming Cells Toward Their Use in Clinical Translation

Recent Advances in Endothelial Colony Forming Cells Toward Their Use in Clinical Translation

Chronic obstructive pulmonary disease: MicroRNAs and exosomes as new diagnostic and therapeutic biomarkers

Decreased miR-24-3p potentiates DNA damage responses and increases susceptibility to COPD

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