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

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

  • Free Radic Biol Med. 2025 Oct 3:241:526-542. doi: 10.1016/j.freeradbiomed.2025.09.057.
Yiwen Wang 1,  Jian Zhang 1,  Yang Gao 1,  Shiyu Hu 1,  Jingpu Wang 1,  Ya'nan Qu 1,  Ji'e Yang 2,  Rong Huang 1,  Hongbo Yang 1,  Wenyuan Zheng 3,  Chenguang Li 4,  Feng Zhang 5,  Jiatian Cao 6,  Junbo Ge 1
Affiliations

Affiliations

  • 1 Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, National Clinical Research Center for Interventional Medicine, Key Laboratory of Viral Heart Diseases, National Health Commission. Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, China.
  • 2 Department of Cardiology, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China.
  • 3 Department of Cardiology, The First Affiliated Hospital of Ningbo University, No.59 Liuting Street, Haishu District, Ningbo, China.
  • 4 Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, National Clinical Research Center for Interventional Medicine, Key Laboratory of Viral Heart Diseases, National Health Commission. Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, China. Electronic address: li.chenguang@zs-hospital.sh.cn.
  • 5 Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, National Clinical Research Center for Interventional Medicine, Key Laboratory of Viral Heart Diseases, National Health Commission. Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, China. Electronic address: zhang.feng@zs-hospital.sh.cn.
  • 6 Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, National Clinical Research Center for Interventional Medicine, Key Laboratory of Viral Heart Diseases, National Health Commission. Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, China. Electronic address: cao.jiatian@zs-hospital.sh.cn.
PMID: 41046944 DOI: 10.1016/j.freeradbiomed.2025.09.057
Abstract

Diabetes mellitus (DM) presents significant public health challenges due to its attribution 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 perfusion 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-transcriptionally represses the elevation. Mechanistically, NOX4 regulates Autophagy through the activation of MAPK signaling. Silencing NOX4 improved AGE-induced endothelial dysfunction 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.

Keywords

Angiogenesis; Apoptosis; Autophagy; Diabetes mellitus; Endothelial cells; Hindlimb ischemia; MAPK signaling; NOX4.

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