TY - JOUR
T1 - Targeting QKI-7 in vivo restores endothelial cell function in diabetes
AU - Yang, Chunbo
AU - Eleftheriadou, Magdalini
AU - Kelaini, Sophia
AU - Morrison, Thomas
AU - González, Marta Vilà
AU - Caines, Rachel
AU - Edwards, Nicola
AU - Yacoub, Andrew
AU - Edgar, Kevin
AU - Moez, Arya
AU - Ivetic, Aleksandar
AU - Zampetaki, Anna
AU - Zeng, Lingfang
AU - Wilkinson, Fiona L.
AU - Lois, Noemi
AU - Stitt, Alan W.
AU - Grieve, David J.
AU - Margariti, Andriana
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85088781219&partnerID=8YFLogxK
U2 - 10.1038/s41467-020-17468-y
DO - 10.1038/s41467-020-17468-y
M3 - Article
C2 - 32732889
AN - SCOPUS:85088781219
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3812
ER -
