Abstract
Dysfunction of endothelial cells (ECs) and their progenitor cells is an important feature of diabetic vascular disease. MicroRNA (miR)-139-5p is involved in inhibiting the metastasis and progression of diverse malignancies. However, the role of miR-139-5p in ECs still remains unclarified. Here we demonstrated that miR-139-5p expression was elevated in endothelial colony-forming cells (ECFCs) isolated from patients with diabetes, ECs derived from the aorta of diabetic rodents, and human umbilical vein endothelial cells (HUVECs) cultured in high glucose media. MiR-139-5p mimics inhibited tube formation, migration, proliferation, and down-regulated expression of c-jun, vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF)-B, in ECFCs and HUVECs, respectively; moreover, miR-139-5p inhibitors reversed the tendency. Further, gain- and-loss function experiments and ChIP assay indicated that miR-139-5p regulate functions of ECFCs by targeting c-jun-VEGF/PDGF-B pathway. In vivo experiments (Matrigel plug assay and hindlimb ischemia model) showed that miR-139-5p downregulation further promoted ECFC-mediated angiogenesis and blood perfusion. In conclusion, diabetes-mediated high miR-139-5p expression inhibits the c-jun-VEGF/PDGF-B pathway, thus decreasing ECFCs migration, tube formation and proliferation, which subsequently reduces ECs survival. Therefore, miR-139-5p might be an important therapeutic target in the treatment of diabetic vasculopathy in the future.
Highlights
Most diabetes-related deaths and disability are due to diabetic vascular complications, including lower extremity critical ischemic, the main cause of limb amputation [1]
endothelial colony-forming cell (ECFC) were isolated and cultured from peripheral blood (PB) of patients with diabetes and healthy adults to test the effects of miR-139-5p on ECFCs in diabetes
Using real-time polymerase chain reaction (PCR), we found miR-139-5p expression in diabetic ECFCs to be 2-fold more than that of healthy subjects
Summary
Most diabetes-related deaths and disability are due to diabetic vascular complications, including lower extremity critical ischemic, the main cause of limb amputation [1]. Endothelial cells (ECs) dysfunction, one of the main features of diabetic vasculopathy, comprises impairment in migration, tube formation, proliferation and angiogenesis, as well as disturbances in vasodilation and vascular integrity [3]. Other hypotheses that delineate the mechanism of ECs dysfunction and subsequent impaired angiogenesis in diabetes include reduction in vascular endothelial growth factor-A (VEGF-A) signaling [4], accumulation of advanced glycation end www.aging-us.com products [5, 6], protein kinase C (PKC) activation [7], sorbitol-inositol imbalance [8], nuclear factor (NF)-κBmediated downstream signaling [9], and the role of angiotensin-II and Peroxisome proliferator-activated receptor-gamma coactivator 1-α (PGC-1α) in the endothelium [10, 11]. Progenitor cells belonging to the endothelial lineage, have been shown to play critical roles in vascular integrity and postnatal vasculogenesis [12]. Such endothelial progenitor cells (EPCs) from adult diabetics are reduced in number, which display blunted proangiogenic properties that impair vascular homeostasis and regeneration [13, 14]
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