miR-223–IGF-IR signalling in hypoxia- and load-induced right-ventricular failure: a novel therapeutic approach

Shi, Lei; Kojonazarov, Baktybek; Elgheznawy, Amro; Popp, Rüdiger; Dahal, Bhola K.; Böhm, Mario; Pullamsetti, Soni Savai; Ghofrani, Hossein Ardeschir; Gödecke, Axel; Jungmann, Andreas; Katus, Hugo A.; Müller, Oliver; Schermuly, Ralph Theo; Fißlthaler, Beate; Seeger, Werner; Fleming, Ingrid

doi:10.1093/cvr/cvw065

Cited by 58 publications

(44 citation statements)

References 51 publications

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“…Changes in miR-322-5p are not the only ones that occur in cardiac hypertrophy that are likely to affect the IGF-1 signalling system. For example, miR-223 is a miRNA that is suppressed by hypoxia but targets the IGF-1R [41]. Overexpression of this miRNA attenuated cardiac hypertrophy and suppressed IGF-1R expression in analogous way to the effects of miR-322-5p in response to MCT.…”

Section: Discussionmentioning

confidence: 97%

miR‐322‐5p targets IGF‐1 and is suppressed in the heart of rats with pulmonary hypertension

et al. 2018

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Pulmonary arterial hypertension ( PAH ) is characterised by remodelling of the pulmonary vasculature leading to right ventricular hypertrophy. Here, we show that miR‐322‐5p (the rodent orthologue of miR‐424‐5p) expression is decreased in the right ventricle of monocrotaline‐treated rats, a model of PAH , whereas a putative target insulin‐like growth factor 1 ( IGF ‐1) is increased. IGF ‐1 mRNA was enriched 16‐fold in RNA immunoprecipitated with Ago2, indicating binding to miR‐322‐5p. In cell transfection experiments, miR‐322‐5p suppressed the activity of a luciferase reporter containing a section of the IGF ‐1 3′ untranslated region ( UTR ) as well as IGF ‐1 mRNA and protein levels. Taken together, these data suggest that miR‐322 targets IGF ‐1, a process downregulated in PAH ‐related RV hypertrophy.

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Section: Discussionmentioning

confidence: 97%

miR‐322‐5p targets IGF‐1 and is suppressed in the heart of rats with pulmonary hypertension

et al. 2018

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“…Recent reports found that miR-223 was down-regulated in human PAH lungs, in both the right heart and lungs from rodent models of PH. Downregulation of miR-223 triggers PARP-1 and insulin-like growth factor 1 receptor (IGF-1R) overexpression, subsequent pathologic DNA damage repair, and increased proliferation [32, 33]. The relationship between miRNAs and target genes in vivo is a complex network.…”

Section: Discussionmentioning

confidence: 99%

Identifying microRNAs targeting Wnt/β-catenin pathway in end-stage idiopathic pulmonary arterial hypertension

Talbot

Liu

et al. 2016

J Mol Med

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MicroRNAs (miRNAs) play important roles in the pathogenesis of pulmonary arterial hypertension (PAH). However, the pathways targeted by miRNAs in PAH have not been systematically investigated. We aim to identify dysregulated miRNAs for patients with idiopathic PAH (IPAH). miRNA profiling was performed on lung tissue total RNA from eight IPAH patients and eight control subjects. Real-time quantitative RT-PCR (qRT-PCR) was used for validation of miRNA and mRNA expression levels in 14 IPAH patients and 14 control subjects. Pathway enrichment analysis showed Wnt/β-catenin signaling is among the top PAH related pathways enriched in target genes of dysregulated miRNAs. We confirmed the significant increased expression levels of 5 miRNAs (let-7a-5p, miR-26b-5p, miR-27b-3p, miR-199a-3p and miR-656) targeting major PAH-related pathways. Moreover, qRT-PCR validation of Wnt/β-catenin pathway activation indicated multiple genes including receptors (FZD4, FZD5), core molecule (CTNNB1), and downstream targets (CCND1, VEGFA and AXIN2) were significantly upregulated. The expression level of miR-199b-5p was positively correlated with patients’ hemodynamics (PVR: p=0.038) and pulmonary vascular remodeling (muscularization: p=0.021). We confirmed overexpression of miR-199b-5p in hypoxic pulmonary arterial endothelial cells that negatively regulates GSK3B expression. In summary, miRNAs influence the pathogenesis of PAH by regulating major PAH related pathways including Wnt/β-catenin in end-stage IPAH.

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“…To test this hypothesis by genetic means, we conducted experiments in iCM-IGF1RKO mice; i.e., mice with an inducible, cardiomyocyte-restricted deletion of the IGF1R gene (Igf1r). 11,12 Compared with WT mice, iCM-IGF1RKO mice did not show differences in cardiac function at baseline ( Figure 3; Table S2). Although IGF1 treatment improved cardiac functional parameters such as EF and FAC (Figures 3B-3D; Table S3) in wild-type (WT) mice after AMI as before, we unexpectedly found that IGF1 treatment also preserved these functional parameters in iCM-IGF1RKO mice.…”

Section: Igf1 Protects the Heart After Ami Independent Of Igf1r Signamentioning

confidence: 95%

IGF1 Treatment Improves Cardiac Remodeling after Infarction by Targeting Myeloid Cells

et al. 2019

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miR-223–IGF-IR signalling in hypoxia- and load-induced right-ventricular failure: a novel therapeutic approach

Cited by 58 publications

References 51 publications

miR‐322‐5p targets IGF‐1 and is suppressed in the heart of rats with pulmonary hypertension

miR‐322‐5p targets IGF‐1 and is suppressed in the heart of rats with pulmonary hypertension

Identifying microRNAs targeting Wnt/β-catenin pathway in end-stage idiopathic pulmonary arterial hypertension

IGF1 Treatment Improves Cardiac Remodeling after Infarction by Targeting Myeloid Cells

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