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

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

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17468-y

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