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

Author(s): Andriana Margariti

Diabetes has become a major health problem worldwide. Vascular Endothelial Cell (EC) dysfunction plays a key role in the occurrence of diabetic complications. The current study discovered significant upregulation of Quaking 7 (QKI-7), in induced pluripotent stem (iPS) cellderived ECs (iPS-ECs) when exposed to hyperglycemia, and in human iPS-ECs from diabetic patients. QKI-7 was also found to be highly expressed in human coronary arterial ECs isolated from diabetic donors, while immunohistochemical staining on blood vessels obtained from diabetic critical limb ischemia patients undergoing a lower limb amputation, QKI-7 expression was detected. QKI-7 expression was found to be tightly controlled by RNA splicing factors CUGBP and hnRNPM under diabetic conditions. QKI-7 upregulation was correlated with disrupted cell barrier, compromised angiogenesis and enhanced monocyte adhesion in diabetic iPS-ECs. RNA immunoprecipitation (RIP) and mRNA decay assays revealed that QKI-7 bound and promoted mRNA degradation of downstream targets CD144, Neuroligin 1 (NLGN1) and tumor necrosis factor (TNF)-α–stimulated gene/protein 6 (TSG-6). Remarkably, when hindlimb ischemia was induced in diabetic mice and QKI-7 was knockdown in vivo in ECs, reperfusion and blood flow recovery were markedly promoted. Manipulation of QKI-7 represents a novel strategy for the treatment of diabetic vascular complications.