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.
Highlights
Vascular endothelial cell (EC) dysfunction plays a key role in diabetic complications
Mouse induced pluripotent stem cell (iPSC) differentiation toward endothelial cells. miPSCs were seeded on collagen IV-coated culture dishes and differentiated toward vascular ECs cultured in differentiation media (α-MEM + 10% fetal bovine serum (FBS)) supplemented with 25 ng/ml vascular endothelial growth factor (VEGF) for 2–10 days
At day 6 of differentiation, flow cytometry demonstrated that 78% of cells were CD144/VE-Cadherin positive, indicating the high efficiency of EC induction from miPSCs (Supplementary Fig. 1D, Supplementary Fig. 12)
Summary
Vascular endothelial cell (EC) dysfunction plays a key role in diabetic complications. Extensive evidence from clinical studies and diabetic animal models revealed the increase of reactive oxygen species (ROS), downregulation of nitric oxide synthase (eNOS), and attenuated nitric oxide (NO) levels in vascular ECs, as important mechanisms underlying the pathogenesis of EC dysfunction[9]. These implicate the involvement of a number of signaling pathways such as PKC, PI3K/AKT, MAPK, NF-kB, and Rho/ROCK amongst others[10,11,12]. A comprehensive understanding of the mechanisms underlying dysfunction of ECs in diabetes is critical to the development of more effective treatments of vascular complications
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