RBPs Play Important Roles in Vascular Endothelial Dysfunction Under Diabetic Conditions

Yang, Chunbo; Kelaini, Sophia; Caines, Rachel; Margariti, Andriana

doi:10.3389/fphys.2018.01310

Cited by 20 publications

(14 citation statements)

References 116 publications

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“…Quaking (QKI) is one of the RBPs related to diabetic cardiomyopathy and atherosclerosis. QKI belongs to the signal transduction and activation of RNA (STAR) family, featuring conserved SH2, SH3, and KH RNA-binding domains and participates in the regulation of pre-mRNA splicing, mRNA nuclear exportation, mRNA stability, protein translation, and signal transduction 19 .…”

Section: Introductionmentioning

confidence: 99%

Targeting QKI-7 in vivo restores endothelial cell function in diabetes

Yang¹,

Eleftheriadou²,

Kelaini³

et al. 2020

Nat Commun

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Vascular endothelial cell (EC) dysfunction plays a key role in diabetic complications. This study discovers significant upregulation of Quaking-7 (QKI-7) in iPS cell-derived ECs when exposed to hyperglycemia, and in human iPS-ECs from diabetic patients. QKI-7 is also highly expressed in human coronary arterial ECs from diabetic donors, and on blood vessels from diabetic critical limb ischemia patients undergoing a lower-limb amputation. QKI-7 expression is tightly controlled by RNA splicing factors CUG-BP and hnRNPM through direct binding. QKI-7 upregulation is correlated with disrupted cell barrier, compromised angiogenesis and enhanced monocyte adhesion. RNA immunoprecipitation (RIP) and mRNA-decay assays reveal that QKI-7 binds and promotes mRNA degradation of downstream targets CD144, Neuroligin 1 (NLGN1), and TNF-α-stimulated gene/protein 6 (TSG-6). When hindlimb ischemia is induced in diabetic mice and QKI-7 is knocked-down in vivo in ECs, reperfusion and blood flow recovery are markedly promoted. Manipulation of QKI-7 represents a promising strategy for the treatment of diabetic vascular complications.

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Section: Introductionmentioning

confidence: 99%

Targeting QKI-7 in vivo restores endothelial cell function in diabetes

Yang¹,

Eleftheriadou²,

Kelaini³

et al. 2020

Nat Commun

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“…For example, RNA-binding motif protein 3 (RBM3) was found to be vital in osteoblast differentiation (Kim et al, 2018), while heterogeneous nuclear ribonucleoprotein K (HNRNPK) has been found to regulate myoblast proliferation and differentiation (Xu et al, 2018). Concurrently, dysregulation of RBP function is implicated in a number of diseases such as diabetes and vascular dysfunction (Yang et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

The RNA-binding protein QKI controls alternative splicing in vascular cells, producing an effective model for therapy

Caines

Cochrane

Kelaini

et al. 2019

Journal of Cell Science

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Dysfunction of endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) leads to ischaemia, the central pathology of cardiovascular disease. Stem cell technology will revolutionise regenerative medicine, but a need remains to understand key mechanisms of vascular differentiation. RNA-binding proteins have emerged as novel post-transcriptional regulators of alternative splicing and we have previously shown that the RNA-binding protein Quaking (QKI) plays roles in EC differentiation. In this study, we decipher the role of the alternative splicing isoform Quaking 6 (QKI-6) to induce VSMC differentiation from induced pluripotent stem cells (iPSCs). PDGF-BB stimulation induced QKI-6, which bound to HDAC7 intron 1 via the QKI-binding motif, promoting HDAC7 splicing and iPS-VSMC differentiation. Overexpression of QKI-6 transcriptionally activated SM22 (also known as TAGLN), while QKI-6 knockdown diminished differentiation capability. VSMCs overexpressing QKI-6 demonstrated greater contractile ability, and upon combination with iPS-ECsoverexpressing the alternative splicing isoform Quaking 5 (QKI-5), exhibited higher angiogenic potential in vivo than control cells alone. This study demonstrates that QKI-6 is critical for modulation of HDAC7 splicing, regulating phenotypically and functionally robust iPS-VSMCs. These findings also highlight that the QKI isoforms hold key roles in alternative splicing, giving rise to cells which can be used in vascular therapy or for disease modelling.This article has an associated First Person interview with the first author of the paper.

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“…Several reports suggest that HuR may be directly involved in the intercellular membrane fusion during development and under the pathological conditions: (i) HuR-deficient mice are embryonic-lethal due to defects in placenta development [ 117 ]; (ii) HuR is essential for the skeletal muscle myotube formations during embryogenesis [ 118 , 119 ]; (iii) HuR contributes to the post-natal pathological angiogenesis via the regulation of pruning of the vascular branches and the endothelial cell self-fusion during this process [ 88 , 120 , 121 , 122 ]; on the other hand, HuR dimerization may promote atherosclerosis and may enhance the permeability of the vascular endothelial layer [ 123 ]; (iv) HuR is essential for the formation of germ cell syncytium where cells stay connected to one another by intercellular bridges [ 124 ]; (v) under the hypoxic condition, HuR enhances epithelial-to-mesenchymal transition, which is associated with intra- and intercellular microtubule formations and could be suppressed by inhibitors of HuR nuclear/cytoplasmic shuttling [ 125 , 126 ]; (vi) HuR promotes integrity of the gap-junction and the stability of Cx43 transcripts, which are involved in the type ii intercellular tunneling nanotube and microtube formations [ 127 , 128 , 129 ]. Collectively, HuR protein dimerization and translocation from the nucleus to the cytoplasm is associated with cell reprogramming toward cell differentiation and intercellular membrane fusion on several occasions during normal development.…”

Section: Potential Pharmacological Modulators Of Cell Fusionmentioning

confidence: 99%

ELAVL1 Role in Cell Fusion and Tunneling Membrane Nanotube Formations with Implication to Treat Glioma Heterogeneity

Filippova

Nabors

2020

Cancers

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Homotypic and heterotypic cell fusions via permanent membrane fusions and temporal tunneling nanotube formations in the glioma microenvironment were recently documented in vitro and in vivo and mediate glioma survival, plasticity, and recurrence. Chronic inflammation, a hypoxic environment, aberrant mitochondrial function, and ER stress due to unfolded protein accumulation upregulate cell fusion events, which leads to tumor heterogeneity and represents an adaptive mechanism to promote tumor cell survival and plasticity in cytotoxic, nutrient-deprived, mechanically stressed, and inflammatory microenvironments. Cell fusion is a multistep process, which consists of the activation of the cellular stress response, autophagy formation, rearrangement of cytoskeletal architecture in the areas of cell-to-cell contacts, and the expression of proinflammatory cytokines and fusogenic proteins. The mRNA-binding protein of ELAV-family HuR is a critical node, which orchestrates the stress response, autophagy formation, cytoskeletal architecture, and the expression of proinflammatory cytokines and fusogenic proteins. HuR is overexpressed in gliomas and is associated with poor prognosis and treatment resistance. Our review provides a link between the HuR role in the regulation of cell fusion and tunneling nanotube formations in the glioma microenvironment and the potential suppression of these processes by different classes of HuR inhibitors.

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RBPs Play Important Roles in Vascular Endothelial Dysfunction Under Diabetic Conditions

Cited by 20 publications

References 116 publications

Targeting QKI-7 in vivo restores endothelial cell function in diabetes

Targeting QKI-7 in vivo restores endothelial cell function in diabetes

The RNA-binding protein QKI controls alternative splicing in vascular cells, producing an effective model for therapy

ELAVL1 Role in Cell Fusion and Tunneling Membrane Nanotube Formations with Implication to Treat Glioma Heterogeneity

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