Identification of MicroRNA-124 as a Major Regulator of Enhanced Endothelial Cell Glycolysis in Pulmonary Arterial Hypertension via PTBP1 (Polypyrimidine Tract Binding Protein) and Pyruvate Kinase M2

Caruso, Paola; Dunmore, Benjamin J.; Schlosser, Kenny; Schoors, Sandra; Santos, Claudia C. dos; Perez‐Iratxeta, Carolina; Lavoie, Jessie R.; Zhang, Hui; Lü, Long; Flockton, Amanda; Frid, Maria G.; Upton, Paul D.; D’Alessandro, Angelo; Hadinnapola, Charaka; Kiskin, Fedir; Taha, Mohamad; Hurst, L; Ormiston, Mark L.; Hata, Akiko; Stenmark, Kurt R.; Carmeliet, Peter; Morrell, Nicholas W.

doi:10.1161/circulationaha.117.028034

Cited by 202 publications

(193 citation statements)

References 52 publications

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“…Recent studies found that miR‐124‐3p is significantly decreased in ECs from pulmonary arterial hypertension (PAH) patients and in various cancers tissues, associated with poor prognosis in patients,35, 36 whose up‐regulation can attenuate glioma cell proliferation, migration and tumour angiogenesis in vitro and in vivo by NRP‐1‐mediated PI3K/AKT/NFκB pathways and by targeting R‐Ras and N‐Ras 35, 37. Meanwhile, it also inhibits angiogenesis and proliferation by targeting Ets‐1 and AKT2 in breast cancer cells 38.…”

Section: Mirnas That Target Genes Involved In Angiogenesismentioning

confidence: 99%

“…Therefore, plasma miR‐424(322) is considered to be a unique value biomarker for the diagnosis and prognostic of PH patients. In addition, miR‐19a expression is significantly elevated in plasma and in PAH lung tissues,184 whereas miR‐124 expression is down‐regulated in blood outgrowth endothelial cells (BOECs) from PAH patients 36. Functionally, elevated miR‐19a can inhibit arteriogenesis by inhibiting Wnt signalling in vitro and in vivo via directly targeting FZD4 and LRP6,81 and miR‐124 play a major role in glycolysis and hyperproliferation of ECs in PAH by regulating PTBP1 and PKM2 36.…”

Section: Clinical Value Of Mirnas As New Biomarkers For Angiogenesis‐mentioning

confidence: 99%

“…In addition, miR‐19a expression is significantly elevated in plasma and in PAH lung tissues,184 whereas miR‐124 expression is down‐regulated in blood outgrowth endothelial cells (BOECs) from PAH patients 36. Functionally, elevated miR‐19a can inhibit arteriogenesis by inhibiting Wnt signalling in vitro and in vivo via directly targeting FZD4 and LRP6,81 and miR‐124 play a major role in glycolysis and hyperproliferation of ECs in PAH by regulating PTBP1 and PKM2 36. In recent studies, miR‐135a levels are up‐regulated in PAH mice models, and miR‐204 and miR‐140‐5p levels are down‐regulated in both PAH patient and PAH model 185, 186.…”

Section: Clinical Value Of Mirnas As New Biomarkers For Angiogenesis‐mentioning

confidence: 99%

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The regulatory role of microRNAs in angiogenesis‐related diseases

Sun

Lei

et al. 2018

J Cellular Molecular Medi

116

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MicroRNAs (miRNAs) are small non‐coding RNAs that regulate gene expression at a post‐transcriptional level via either the degradation or translational repression of a target mRNA. They play an irreplaceable role in angiogenesis by regulating the proliferation, differentiation, apoptosis, migration and tube formation of angiogenesis‐related cells, which are indispensable for multitudinous physiological and pathological processes, especially for the occurrence and development of vascular diseases. Imbalance between the regulation of miRNAs and angiogenesis may cause many diseases such as cancer, cardiovascular disease, aneurysm, Kawasaki disease, aortic dissection, phlebothrombosis and diabetic microvascular complication. Therefore, it is important to explore the essential role of miRNAs in angiogenesis, which might help to uncover new and effective therapeutic strategies for vascular diseases. This review focuses on the interactions between miRNAs and angiogenesis, and miRNA‐based biomarkers in the diagnosis, treatment and prognosis of angiogenesis‐related diseases, providing an update on the understanding of the clinical value of miRNAs in targeting angiogenesis.

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Section: Mirnas That Target Genes Involved In Angiogenesismentioning

confidence: 99%

Section: Clinical Value Of Mirnas As New Biomarkers For Angiogenesis‐mentioning

confidence: 99%

Section: Clinical Value Of Mirnas As New Biomarkers For Angiogenesis‐mentioning

confidence: 99%

See 1 more Smart Citation

The regulatory role of microRNAs in angiogenesis‐related diseases

Sun

Lei

et al. 2018

J Cellular Molecular Medi

116

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“…To date, a large body of evidence has pointed to the functional role of miRNAs in the pathophysiology of PAH. Caruso et al showed that miR‐124 was down‐regulated in the pulmonary vascular and circulating progenitor endothelial cells from PAH patients, and dysregulation of miR‐124 contributed to the endothelial cell glycolysis . miR‐4224 and miR‐503 were found to mediate the link between endothelial apelin and fibroblast growth factor 2, which was disrupted in the PAH .…”

Section: Introductionmentioning

confidence: 99%

MiR‐629 regulates hypoxic pulmonary vascular remodelling by targeting FOXO3 and PERP

Zhao

Chen

et al. 2019

J Cellular Molecular Medi

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Pulmonary arterial hypertension (PAH) is featured by the increase in pulmonary vascular resistance and pulmonary arterial pressure. Despite that abnormal proliferation and phenotypic changes in human pulmonary artery smooth muscle cells (HPASMCs) contributing to the pathophysiology of PAH, the underlying molecular mechanisms remain unclear. In the present study, we detected the expression of miR‐629 in hypoxia‐treated HPASMCs and explored the mechanistic role of miR‐629 in regulating HPASMC proliferation, migration and apoptosis. Hypoxia time‐dependently induced up‐regulation of miR‐629 and promoted cell viability and proliferation in HPASMCs. Treatment with miR‐629 mimics promoted HPASMCs proliferation and migration, but inhibited cell apoptosis; while knockdown of miR‐629 suppressed the cell proliferation and migration but promoted cell apoptosis in HPASMCs. The bioinformatics prediction revealed FOXO3 and PERP as downstream targets of miR‐629, and miR‐629 negatively regulated the expression of FOXO3 and PERP via targeting the 3’ untranslated regions. Enforced expression of FOXO3 or PERP attenuated the miR‐629 overexpression or hypoxia‐induced enhanced effects on HPASMC proliferation and proliferation, and the suppressive effects on HPASMC apoptosis. Furthermore, the expression of miR‐629 was up‐regulated, and the expression of FOXO3 and PERP mRNA was down‐regulated in the plasma from PAH patients when compared to healthy controls. In conclusion, the present study provided evidence regarding the novel role of miR‐629 in regulating cell proliferation, migration and apoptosis of HPASMCs during hypoxia.

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“…Glycolysis is a central element of the primary metabolic activity and generates biomass precursors and energy from sugars which is a key element in the metabolism of mammalian cells (Rehberg, Ritter, & Reichl, ). Antiapoptotic and highly proliferative cells exhibit a shift from glucose oxidation to lactate synthesis and aerobic glycolysis, accompanied by upregulation of cytoplasmic glycolysis (Caruso et al, ; Sun et al, ). This phenomenon, known as the “Warburg effect,” was observed in colon and pancreatic tumors and patients with pulmonary arterial hypertension (de Alteriis, Carteni, Parascandola, Serpa, & Mazzoleni, ; Sithara, Arun, Syama, Reshmitha, & Nisha, ; W. H. Zhang et al, ).…”

Section: Introductionmentioning

confidence: 99%

Lipopolysaccharide‐induced proliferation and glycolysis in airway smooth muscle cells via activation of Drp1

Zhang

Wang

et al. 2018

Journal Cellular Physiology

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Abnormal airway smooth muscle cells (ASMCs) proliferation is an important pathological process in airway remodeling contributes to increased mortality in asthma. Mitochondrial dynamics and metabolism have a central role in the maintenance of the cell function. In this study, lipopolysaccharide (LPS)‐induced ASMCs proliferative model was used to investigate the effect of mitochondria on the proliferation of ASMCs and the possible mechanism. We used cell and molecular biology to determine the effect of dynamin‐related protein 1 (Drp1) on LPS‐mediated ASMCs cell cycle progression and glycolysis. The major findings of the current study are as follows: LPS promoted an increased mitochondrial fission and phosphorylation of Drp1 at Ser616 (p‐Drp1 Ser616). LPS‐induced ASMCs proliferation and cell cycle progression, which was significantly inhibited application of Drp1 RNA interfering. Glycolysis inhibitor 2‐deoxyglucose (2‐DG) depressed ASMCs proliferative process induced by LPS stimulation. LPS caused mitochondrial metabolism disorders and aerobic glycolysis in a dependent on Drp1 activation. These results indicated that Drp1 may function as a key factor in asthma airway remodeling by mediating ASMC proliferation and cell cycle acceleration through an effect on mitochondrial metabolic disturbance.

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Identification of MicroRNA-124 as a Major Regulator of Enhanced Endothelial Cell Glycolysis in Pulmonary Arterial Hypertension via PTBP1 (Polypyrimidine Tract Binding Protein) and Pyruvate Kinase M2

Cited by 202 publications

References 52 publications

The regulatory role of microRNAs in angiogenesis‐related diseases

The regulatory role of microRNAs in angiogenesis‐related diseases

MiR‐629 regulates hypoxic pulmonary vascular remodelling by targeting FOXO3 and PERP

Lipopolysaccharide‐induced proliferation and glycolysis in airway smooth muscle cells via activation of Drp1

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