MiRNA-27a-5p alleviates diabetic vascular injury via modulating autophagy by targeting NOX4.

Diabetes mellitus (DM) presents significant public health challenges due to its contribution to high rates of disability and mortality through vascular complications. While many microRNAs (miRNAs) regulate endothelial homeostasis and contribute to vascular repair, their roles in diabetic endothelial injury have not been fully elucidated. Among these, miRNA-27a-5p (miR-27a-5p) is abundant in endothelial cells; yet its specific function in the context of diabetes remains unclear. This study specifically investigates the protective role of miR-27a-5p against diabetic vascular injury and its effects on autophagy and endothelial cell function. We observed that hyperglycemia-induced advanced glycation end-products (AGEs) induce excessive apoptosis and autophagy, leading to endothelial dysfunction by mediating reactive oxygen species (ROS) production. MiR-27a-5p overexpression promotes blood flow recovery in diabetic mice following hindlimb ischemia (HLI) through alleviating excessive autophagy and restoring endothelial dysfunction. Utilizing RNA sequencing and miRwalk analyses, we identified NADPH oxidase 4 (NOX4) as a direct target of miR-27a-5p. AGEs induce NOX4 expression, whereas miR-27a-5p post-transcriptional repress the elevation. Mechanistically, NOX4 regulates autophagy through the activation of MAPK signaling. Silencing NOX4 improved AGE-induced endothelial function by regulating apoptosis and autophagy. Collectively, these findings underscore the protective role of miR-27a-5p against vascular injury by modulating NOX4, highlighting it as a promising therapeutic target for the management of diabetic vascular complications.