Abstract
Dysfunction of endothelial progenitor cells (EPCs) is a key factor in vascular complications of diabetes mellitus. Although the roles of microRNAs and circular RNAs in regulating cell functions have been thoroughly studied, their role in regulating autophagy and apoptosis of EPCs remains to be elucidated. This study investigated the roles of mir-20a-5p and its predicted target circ-ADAM9 in EPCs treated with high glucose (30 mM) and in a diabetic mouse hind limb ischemia model. It is found that Mir-20a-5p inhibited autophagy and apoptosis of EPCs induced by high-concentration glucose. Further, mir-20a-5p could inhibit the expression of PTEN and ATG7 in EPCs, and promote the phosphorylation of AKT and mTOR proteins under high-glucose condition. Investigation of the underlying mechanism revealed that circ-ADAM9, as a miRNA sponges of mir-20a-5p, promoted autophagy and apoptosis of EPCs induced by high-concentration glucose. Circ-ADAM9 upregulated PTEN and ATG7 in interaction with mir-20a-5p, and inhibited the phosphorylation of AKT and mTOR to aggravate autophagy and apoptosis of EPCs under high glucose. In addition, silencing of circ-ADAM9 increased microvessel formation in the hind limbs of diabetic mice. Our findings disclose a novel autophagy/apoptosis-regulatory pathway that is composed of mir-20a-5p, circ-ADAM9, PTEN, and ATG7. Circ-ADAM9 is a potential novel target for regulating the function of diabetic EPCs and angiogenesis.
Highlights
Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia
Western blot analysis revealed that knockdown of PTEN as well as treatment with the autophagy inhibitor 3methyladenine (3-MA) counteracted the inhibitory effect of circ-ADAM9 on p-AKT and p-mTOR levels (Fig. 6d, e). These results indicated that circ-ADAM9 targets PTENregulated AKT/mTOR signaling and directly targets the autophagy-related gene autophagy-related gene 7 (ATG7) to regulate autophagy and apoptosis of endothelial progenitor cells (EPCs) under high-glucose condition
EPCs have a key role in the repair of endothelial dysfunction by secreting a variety of growth factors or differentiating into mature endothelial cells
Summary
Diabetic macro- and microvascular complications are the main causes of death and disability in patients with diabetes mellitus, and endothelial dysfunction is one of the major causes of diabetic vascular complications[1]. A reduction in EPCs can lead to vascular endothelial dysfunction, as has been observed in patients with diabetes[4]. Autophagy is an evolutionarily conserved stress response[5,6]. It is generally considered a protective mechanism because it provides nutrition for cells and eliminates damaged organelles. Autophagy can lead to excessive consumption of intracellular proteins and organelles as well as the degradation of anti-apoptotic and cell-survival factors, resulting in autophagic cell death and apoptosis[7,8,9].
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