MicroRNA-200a improves diabetic endothelial dysfunction by targeting KEAP1/NRF2.

Area of Science:

• Endocrinology
• Molecular Biology
• Cellular Biology

Background:

• Diabetic macrovascular complications cause high mortality, with endothelial dysfunction (ED) being a critical early step.
• Oxidative stress (OS) drives ED, and Nuclear factor erythroid 2-related factor 2 (NRF2) is a key regulator of antioxidant defense against diabetes-induced OS.
• Previous studies indicated impaired NRF2 signaling contributes to diabetic ED.

Purpose of the Study:

• To investigate the role of microRNA-200a (miR-200a) in regulating NRF2 signaling and its impact on diabetic endothelial dysfunction.
• To elucidate the molecular mechanism by which miR-200a influences the Keap1/NRF2 pathway in endothelial cells under high glucose conditions.

Main Methods:

• Isolated aortic endothelial cells (ECs) from wild-type (WT) and Nrf2 knockout (KO) mice.
• Utilized high glucose (HG) models, miR-200a mimics (miR-200a-M) and inhibitors, and Keap1 knockdown.
• Assessed expression levels of miR-200a, Keap1, and NRF2, alongside markers of OS and inflammation, both in vitro and in vivo.

Main Results:

• High glucose reduced miR-200a and increased Keap1, inhibiting NRF2 signaling and promoting OS/inflammation in WT ECs.
• miR-200a mimic administration reversed these effects by targeting Keap1, confirming Keap1 as a miR-200a target.
• The protective effects of miR-200a were dependent on NRF2, as they were abolished in Nrf2 KO mice and Nrf2 KO in vivo models.
• In vivo, miR-200a-M activated NRF2 signaling and attenuated hyperglycemia-induced ED, OS, and inflammation in WT mice.

Conclusions:

• The study identifies a novel miR-200a/KEAP1/NRF2 signaling axis that regulates endothelial antioxidant capacity.
• This pathway is crucial for protecting against diabetic endothelial dysfunction.
• Targeting miR-200a represents a potential therapeutic strategy for managing diabetic macrovascular complications.