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

  • Nat Commun. 2020 Jul 30;11(1):3812. doi: 10.1038/s41467-020-17468-y.
Chunbo Yang  1 ,  Magdalini Eleftheriadou  1 ,  Sophia Kelaini  1 ,  Thomas Morrison  1 ,  Marta Vilà González  1 ,  Rachel Caines  1 ,  Nicola Edwards  2 ,  Andrew Yacoub  1 ,  Kevin Edgar  1 ,  Arya Moez  1 ,  Aleksandar Ivetic  3 ,  Anna Zampetaki  3 ,  Lingfang Zeng  3 ,  Fiona L Wilkinson  2 ,  Noemi Lois  1 ,  Alan W Stitt  1 ,  David J Grieve  1 ,  Andriana Margariti  4
Affiliations
  • 1. The Wellcome-Wolfson Institute of Experimental Medicine, Belfast, BT9 7BL, UK.
  • 2. Centre for Bioscience in the Department of Life Sciences, Faculty of Science and Engineering, Manchester Metropolitan University, Manchester, M15GD, UK.
  • 3. School of Cardiovascular Medicine and Sciences, BHF Centre of Research Excellence, King's College London, The James Black Centre, 125 Coldharbour Lane, London, SE5 9NU, UK.
  • 4. The Wellcome-Wolfson Institute of Experimental Medicine, Belfast, BT9 7BL, UK. [email protected].
PMID: 32732889 DOI: 10.1038/s41467-020-17468-y
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.