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

Yang, Chunbo; Eleftheriadou, Magdalini; Kelaini, Sophia; Morrison, Thomas; Vilà‐González, Marta; Caines, Rachel; Edwards, Nicola; Yacoub, Andrew; Edgar, Kevin; Moez, Arya; Ivetic, Aleksandar; Zampetaki, Anna; Zeng, Lingfang; Wilkinson, Fiona L.; Lois, Noemi; Stitt, Alan W.; Grieve, David; Margariti, Andriana

doi:10.1038/s41467-020-17468-y

Cited by 46 publications

(49 citation statements)

References 70 publications

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“…In addition, as we have also reported [ 21 ], QKI5 played a crucial role in differentiating ECs from induced pluripotent stem cells (iPSCs) via stabilization of VE-cadherin and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) activation through Signal Transducer and Activator of Transcription 3 (STAT3) signaling. Furthermore, we showed QKI-7 to bind and promote mRNA target degradation such as of VE-cadherin, while the knockdown of QKI7 in a diabetic mouse model of hindlimb ischemia significantly restored reperfusion and blood flow in vivo [ 22 ].…”

Section: Rbps In the Pathogenesis Of Diabetes And Cardiovascular Diseasementioning

confidence: 99%

RNA-Binding Proteins Hold Key Roles in Function, Dysfunction, and Disease

Kelaini

Chan

Cornelius

et al. 2021

Biology

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RNA-binding proteins (RBPs) are multi-faceted proteins in the regulation of RNA or its RNA splicing, localisation, stability, and translation. Amassing proof from many recent and dedicated studies reinforces the perception of RBPs exerting control through differing expression levels, cellular localization and post-transcriptional alterations. However, since the regulation of RBPs is reliant on the micro-environment and events like stress response and metabolism, their binding affinities and the resulting RNA-RBP networks may be affected. Therefore, any misregulation and disruption in the features of RNA and its related homeostasis can lead to a number of diseases that include diabetes, cardiovascular disease, and other disorders such as cancer and neurodegenerative diseases. As such, correct regulation of RNA and RBPs is crucial to good health as the effect RBPs exert through loss of function can cause pathogenesis. In this review, we will discuss the significance of RBPs and their typical function and how this can be disrupted in disease.

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Section: Rbps In the Pathogenesis Of Diabetes And Cardiovascular Diseasementioning

confidence: 99%

RNA-Binding Proteins Hold Key Roles in Function, Dysfunction, and Disease

Kelaini

Chan

Cornelius

et al. 2021

Biology

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“…In a different study, RNA-binding protein Quaking-7 (QKI-7) was found to be upregulated in iPSC-ECs after exposure to hyperglycemia and in hiPSC-ECs from diabetic patients. QKI-7 upregulation was correlated with disrupted cell barrier, enhanced monocyte adhesion, and compromised angiogenesis, suggesting this protein as a possible new strategy for the treatment of diabetic vascular complications [105]. Another approach could be the use of information from genome-wide association studies (GWAS), which have successfully identified a large number of genetic loci associated with risks of complex traits in cardiovascular diseases.…”

Section: Complex Vascular Disease-diabetesmentioning

confidence: 99%

Hypoxia as a Driving Force of Pluripotent Stem Cell Reprogramming and Differentiation to Endothelial Cells

et al. 2020

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Inadequate supply of oxygen (O2) is a hallmark of many diseases, in particular those related to the cardiovascular system. On the other hand, tissue hypoxia is an important factor regulating (normal) embryogenesis and differentiation of stem cells at the early stages of embryonic development. In culture, hypoxic conditions may facilitate the derivation of embryonic stem cells (ESCs) and the generation of induced pluripotent stem cells (iPSCs), which may serve as a valuable tool for disease modeling. Endothelial cells (ECs), multifunctional components of vascular structures, may be obtained from iPSCs and subsequently used in various (hypoxia-related) disease models to investigate vascular dysfunctions. Although iPSC-ECs demonstrated functionality in vitro and in vivo, ongoing studies are conducted to increase the efficiency of differentiation and to establish the most productive protocols for the application of patient-derived cells in clinics. In this review, we highlight recent discoveries on the role of hypoxia in the derivation of ESCs and the generation of iPSCs. We also summarize the existing protocols of hypoxia-driven differentiation of iPSCs toward ECs and discuss their possible applications in disease modeling and treatment of hypoxia-related disorders.

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“…Under hypoxia, QKI directly regulated hypoxia‐induced factor‐1a (HIF‐1α) expression to support tumorigenesis 14 . QKI isoforms have also been implicated in altering vascular endothelial growth factor receptor (VEGF‐R)/ Neuropilin‐1 (NRP1) co‐receptor signalling pathway in endothelial cell differentiation and functions 15,16 . They can compete with microRNAs to inhibit gene expression of NRP‐1/2 that are essential for early cell development 13 .…”

Section: Introductionmentioning

confidence: 99%

NRP1 and MMP9 are dual targets of RNA‐binding protein QKI5 to alter VEGF‐R/ NRP1 signalling in trophoblasts in preeclampsia

Yang

Chen

et al. 2021

J Cellular Molecular Medi

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Preeclampsia (PE) is characterized by placental ischemia and hypoxia, resulting in abnormal casting of the uterine spiral artery, which is mainly caused by insufficient trophoblastic cell infiltration. A reduction in levels of growth factor‐based signalling via Neuropilin‐1 (NRP1) has been shown to contribute to dysfunctional trophoblast development. In this study, we showed that the RNA‐binding protein, QKI5, regulated NRP1 expression and significantly improved trophoblast proliferation in vitro and in vivo. QKI5 and NRP1 expressions were significantly reduced in human PE placentas and in trophoblasts during hypoxia. Overexpression of these factors significantly improved cell proliferation and migration in vitro, in contrast to a decrease upon siRNA knockdown of QKI5 and NRP1 in HTR‐8/SVneo cells. Using RIP and RNA pull‐down assays, we further showed that QKI5 directly interacted with the 3'‐UTR region of NRP1, to mediate cell proliferation and migration via matrix metalloprotease‐9. Further, similar to NRP1, QKI5 also targets matrix metalloproteinase 9 (MMP9) involved in secretion of growth factors and its effects can be counteracted by NRP1 overexpression. In vivo studies using a PE mouse model revealed that QKI5 overexpression alleviated PE‐related symptoms such as elevated blood pressure and proteinuria. Taken together, we found that QKI5 was a novel regulator, of VEGF‐R/NRP1 signalling pathway functioning in trophoblast proliferation and migration, resulting in major contributors to the pathogenesis of PE. While careful evaluation of the broad implications of QKI5 expression is still necessary, this study identified QKI5 as a promising target for treatment strategies in acute PE patients.

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

Cited by 46 publications

References 70 publications

RNA-Binding Proteins Hold Key Roles in Function, Dysfunction, and Disease

RNA-Binding Proteins Hold Key Roles in Function, Dysfunction, and Disease

Hypoxia as a Driving Force of Pluripotent Stem Cell Reprogramming and Differentiation to Endothelial Cells

NRP1 and MMP9 are dual targets of RNA‐binding protein QKI5 to alter VEGF‐R/ NRP1 signalling in trophoblasts in preeclampsia

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