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

Author

Listed:
  • Chunbo Yang

    (The Wellcome-Wolfson Institute of Experimental Medicine)

  • Magdalini Eleftheriadou

    (The Wellcome-Wolfson Institute of Experimental Medicine)

  • Sophia Kelaini

    (The Wellcome-Wolfson Institute of Experimental Medicine)

  • Thomas Morrison

    (The Wellcome-Wolfson Institute of Experimental Medicine)

  • Marta Vilà González

    (The Wellcome-Wolfson Institute of Experimental Medicine)

  • Rachel Caines

    (The Wellcome-Wolfson Institute of Experimental Medicine)

  • Nicola Edwards

    (Manchester Metropolitan University)

  • Andrew Yacoub

    (The Wellcome-Wolfson Institute of Experimental Medicine)

  • Kevin Edgar

    (The Wellcome-Wolfson Institute of Experimental Medicine)

  • Arya Moez

    (The Wellcome-Wolfson Institute of Experimental Medicine)

  • Aleksandar Ivetic

    (The James Black Centre)

  • Anna Zampetaki

    (The James Black Centre)

  • Lingfang Zeng

    (The James Black Centre)

  • Fiona L. Wilkinson

    (Manchester Metropolitan University)

  • Noemi Lois

    (The Wellcome-Wolfson Institute of Experimental Medicine)

  • Alan W. Stitt

    (The Wellcome-Wolfson Institute of Experimental Medicine)

  • David J. Grieve

    (The Wellcome-Wolfson Institute of Experimental Medicine)

  • Andriana Margariti

    (The Wellcome-Wolfson Institute of Experimental Medicine)

Abstract

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.

Suggested Citation

  • Chunbo Yang & Magdalini Eleftheriadou & Sophia Kelaini & Thomas Morrison & Marta Vilà González & Rachel Caines & Nicola Edwards & Andrew Yacoub & Kevin Edgar & Arya Moez & Aleksandar Ivetic & Anna Zam, 2020. "Targeting QKI-7 in vivo restores endothelial cell function in diabetes," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17468-y
    DOI: 10.1038/s41467-020-17468-y
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    Cited by:

    1. Sara G. Romeo & Ilaria Secco & Edoardo Schneider & Christina M. Reumiller & Celio X. C. Santos & Anna Zoccarato & Vishal Musale & Aman Pooni & Xiaoke Yin & Konstantinos Theofilatos & Silvia Cellone Tr, 2023. "Human blood vessel organoids reveal a critical role for CTGF in maintaining microvascular integrity," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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