Downregulation of MicroRNA-126 Contributes to the Failing Right Ventricle in Pulmonary Arterial Hypertension

Potus, François; Ruffenach, Grégoire; Dahou, Abdellaziz; Thébault, Christophe; Breuils‐Bonnet, Sandra; Tremblay, Ève; Nadeau, Valérie; Paradis, Renée; Graydon, Colin; Wong, Randall; Johnson, Ian; Paulin, Roxane; Lajoie, Annie C.; Perron, Jean; Charbonneau, Éric; Joubert, Philippe; Pîbarot, Philippe; Michelakis, Evangelos D.; Provencher, Steeve; Bonnet, Sébastien

doi:10.1161/circulationaha.115.016382

Cited by 179 publications

(188 citation statements)

References 49 publications

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“…Similarly, Potus and colleagues [45] discover that miR-126-3p can improve right heart function in patients with pulmonary hypertension through the Ras/extracellular signal-regulated kinase (ERK)/VEGF pathway by targeting Spred1. underlying mechanism might be that miR-126-3p upregulation increases right heart microvessel density.…”

Section: Discussionmentioning

confidence: 99%

WITHDRAWN: Screened microRNAs related to endothelial progenitor cells and verified the target gene of microRNA-126-3p

Deng¹,

Xu²,

Li³

et al. 2018

Oncotarget

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Background: Endothelial progenitor cell play a vital role in neovascularization. Exercise-based cardiac rehabilitation significantly increases endothelial progenitor cells number and functions in patients with ischemic disease. Exercise can also increase the level of endothelial microRNAs. We hypothesized that microRNAs participate in regulating endothelial progenitor cell function under aerobic exercise. Thus, we attempted to identify such microRNAs and to verify the miR-126-3p target gene.Methods: Microarray is used to screen the microRNAs. The prediction programs TargetScan is used to predict the miR-126-3p target gene. Experimental EPCs are treated with miR-126-3p mimics. The relative expression of miR-126-3p and Mus musculus sprouty-related EVH1 domain-containing 1 (Spred1) are examined using real-time PCR and western blot. The dual-luciferase reporter assay is used to verify the miR-126-3p target gene.Results: The miR-126-3p target genes included those contributing to angiogenesis and revascularization. The predicted miR-126-3p target gene is Spred1. Compared with the control, miR-126-3p relative expression is highest following 48-h treatment with 50 nM miR-126-3 mimic. Spred1 mRNA and protein expression in the experimental group is 40.7% and 45.7%. The ratio of Renilla and firefly luciferase activity in the wild-type group is 88.3% and 74.2% of the control respectively (all, n = 3, p < 0.001).Conclusion: miR-126-3p participates in regulating endothelial progenitor cell function after aerobic exercise. MiR-126-3p inhibits the transcription and translation of Spred1, the target gene of miR-126-3p.

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Section: Discussionmentioning

confidence: 99%

WITHDRAWN: Screened microRNAs related to endothelial progenitor cells and verified the target gene of microRNA-126-3p

Deng¹,

Xu²,

Li³

et al. 2018

Oncotarget

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“…A recent study showed that patients with CAD have lower circulating levels of miR-126, likely playing a role in plaque instability. 47 In PAH, miR-126 was also described as an important player of endothelial integrity and its downregulation in patients with PAH led to decreased vascular density in the RV 33 and peripheral muscle. 32 Thus, these epigenetic alterations may also increase the susceptibility of patients with PAH to develop CAD.…”

Section: Discussionmentioning

confidence: 99%

“…This concept is not surprising because PAH is now recognized not to be restricted to the lungs. [31][32][33][34] Therefore, we hypothesize that sustained activation of BRD4 during PAH will progressively contribute to coronary alterations (CAD or MVD) in these vulnerable patients. This may be attributable to detrimental conditions, such as increased inflammation, known to cause DNA damage and activate this epigenetic reader, 15,17,35 that propagate to the coronary arteries and activate the BRD4 axis in the heart.…”

Section: P Ulmonary Arterial Hypertension (Pah) Is a Vascularmentioning

confidence: 99%

Implication of Inflammation and Epigenetic Readers in Coronary Artery Remodeling in Patients With Pulmonary Arterial Hypertension

Meloche

Lampron

Nadeau

et al. 2017

ATVB

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P ulmonary arterial hypertension (PAH) is a vascularremodeling disease (VRD) first described as an obstructive pathology affecting the distal pulmonary arteries. It is characterized by enhanced inflammation, vasoconstriction, and proliferation/apoptosis imbalance within the arterial wall, leading to increased pulmonary vascular resistance and right ventricular (RV) failure and death. 1 The smooth muscle cells (SMCs) within the pulmonary arterial wall exhibit exaggerated proliferation and resistance to apoptosis. Many groups have studied the underlying mechanisms of this "cancer-like" phenotype to find better ways to treat this deadly disease. The similarities in histological features between PAH and other VRDs suggest common pathogenic mechanisms. We and others have described the implication of the receptor of advanced glycation endproducts, 2-4 the oncoprotein kinase Pim-1 3, 5 and the transcription factor nuclear factor of activated T cells 6,7 in promoting proliferation in remodeling processes occurring in both VRD and PAH. In PAH patients' lung vasculature, these molecular actors are, at least in part, regulated by proinflammatory cytokines, alterations in the miR-223/DNA damage/ Poly[ADP-ribose] polymerase 1/miR-204 axis 8-11 and subsequent overexpression of the epigenetic reader bromodomain protein 4 (BRD4). 12 BRD4 functions as a scaffold for transcription factors at promoters and superenhancers, modulating the chromatin landscape and facilitating transcriptional activation of target genes. 13 Interestingly, BRD4 is also implicated in systemic VRD by triggering proinflammatory endothelial © 2017 American Heart Association, Inc. Objective-Pulmonary arterial hypertension (PAH) is a vascular disease not restricted to the lungs. Many signaling pathways described in PAH are also of importance in other vascular remodeling diseases, such as coronary artery disease (CAD). Intriguingly, CAD is 4× more prevalent in PAH compared with the global population, suggesting a link between these 2 diseases. Both PAH and CAD are associated with sustained inflammation and smooth muscle cell proliferation/ apoptosis imbalance and we demonstrated in PAH that this phenotype is, in part, because of the miR-223/DNA damage/ Poly[ADP-ribose] polymerase 1/miR-204 axis activation and subsequent bromodomain protein 4 (BRD4) overexpression. Interestingly, BRD4 is also a trigger for calcification and remodeling processes, both of which are important in CAD. Thus, we hypothesize that BRD4 activation in PAH influences the development of CAD. Approach and Results-PAH was associated with significant remodeling of the coronary arteries in both human and experimental models of the disease. As observed in PAH distal pulmonary arteries, coronary arteries of patients with PAH also exhibited increased DNA damage, inflammation, and BRD4 overexpression. In vitro, using human coronary artery smooth muscle cells from PAH, CAD and non-PAH-non-CAD patients, we showed that both PAH and CAD smooth muscle cells exhibited increased proliferation and suppres...

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“…Administration of miR-126 mimics ameliorates microvascular density, improves RV function and diminishes fibrosis, whereas antagomiR-mediated miR-126 downregulation exacerbates RV failure. 39 Recent research by Halkein et al proposed the 16-kDa N-terminal fragment of the nursing hormone prolactin (16K PRL) as a potential factor initiating and driving peripartum cardiomyopathy (PPCM). Expression of miR-146a is induced in endothelial cells (ECs) by 16K PRL.…”

Section: Heart Failurementioning

confidence: 99%

MicroRNA in cardiovascular biology and disease

Wojciechowska¹,

Braniewska²,

2017

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MicroRNAs (miRNAs) are members of a non-coding RNA family. They act as negative regulators of protein translation by affecting messenger RNA (mRNA) stability; they modulate numerous signaling pathways and cellular processes, and are involved in cell-to-cell communication. Thus, studies on miRNAs offer an opportunity to improve our understanding of complex biological mechanisms. In the cardiovascular system, miRNAs control functions of various cells, such as cardiomyocytes, endothelial cells, smooth muscle cells and fibroblasts. The pivotal role of miRNAs in the cardiovascular system provides a new perspective on the pathophysiology of disorders like myocardial infarction, hypertrophy, fibrosis, heart failure, arrhythmia, inflammation and atherosclerosis. MiRNAs are differentially expressed in diseased tissue and can be released into circulation. Manipulation of miRNA activity may influence the course of a disease. Therefore, miRNAs have become an active field of research for developing new diagnostic and therapeutic tools. This review discusses emerging functions of miRNAs in cardiogenesis, heart regeneration and the pathophysiology of cardiovascular diseases.

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Downregulation of MicroRNA-126 Contributes to the Failing Right Ventricle in Pulmonary Arterial Hypertension

Cited by 179 publications

References 49 publications

WITHDRAWN: Screened microRNAs related to endothelial progenitor cells and verified the target gene of microRNA-126-3p

WITHDRAWN: Screened microRNAs related to endothelial progenitor cells and verified the target gene of microRNA-126-3p

Implication of Inflammation and Epigenetic Readers in Coronary Artery Remodeling in Patients With Pulmonary Arterial Hypertension

MicroRNA in cardiovascular biology and disease

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