miR-222-3p inhibits diabetic skin wound healing by targeting APLN

Abstract

Diabetic foot ulcer (DFU) is a severe complication of diabetes, characterized by chronic, difficult-to-heal foot wounds. It has been hypothesized that miR-222-3p may influence wound healing via the regulation of angiogenesis. To elucidate the underlying mechanism, experimental investigations were conducted in vitro using human dermal microvascular endothelial cells (HMEC-1) and in vivo in a mouse model of streptozotocin-induced diabetes. Methylglyoxal (MGO), a glycolytic intermediate, is known to contribute to diabetic vascular complications. The results demonstrated that MGO-treated HMEC-1 cells exhibited an increased expression of miR-222-3p and impaired microvascular endothelial cell function. The overexpression of miR-222-3p in MGO-treated HMEC-1 cells further suppressed cell proliferation, migration and tube formation, while it enhanced apoptosis. Moreover, the upregulation of miR-222-3p reduced the expression of apelin (APLN), and dual-luciferase reporter assays confirmed APLN as a direct downstream target of miR-222-3p. The silencing of APLN markedly impaired HMEC-1 cell function. Notably, both the exogenous supplementation with Apelin-13 and the overexpression of APLN significantly reversed endothelial dysfunction caused by the upregulation of miR-222-3p. In vivo, in both normal and diabetic mice, the elevated expression of miR-222-3p in skin wounds reduced APLN levels in the peri-wound tissue and impaired wound healing. However, the overexpression of APLN or the inhibition of miR-222-3p with an antagomiR reversed this impairment. Collectively, these results suggest that miR-222-3p impairs microvascular endothelial cell function by targeting APLN, thereby contributing to delayed wound healing in diabetic skin.