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

2020/02/07 by Ziping Jiang, Junduo Wu, Fuzhe Ma +8 · 33 citations
Biochemistry, Genetics and Molecular Biology · Chemistry · Medicine · #Apoptosis #Biochemistry #Biology #Cardiovascular, Neuropeptides, and Oxidative Stress Research #Cell biology #Chemistry #Diabetes mellitus #Endocrinology #Endothelial dysfunction #Gene knockdown #Genomics, phytochemicals, and oxidative stress #Inflammation #Internal medicine #KEAP1 #Medicine #MicroRNA in disease regulation #Oxidative stress #Pharmacology #Regulator #Signal transduction #Transcription factor #microRNA

paper · doi:10.1530/joe-19-0414

published in Journal of Endocrinology 245(1), 129-140 (Bioscientifica)

openalex publication_date 2020/02/07 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/25

Abstract

Over a half of the diabetic individuals develop macrovascular complications that cause high mortality. Oxidative stress (OS) promotes endothelial dysfunction (ED) which is a critical early step toward diabetic macrovascular complications. Nuclear factor erythroid 2-related factor 2 (NRF2) is a master regulator of cellular antioxidant defense system and combats diabetes-induced OS. Previously, we found that impaired NRF2 antioxidant signaling contributed to diabetes-induced endothelial OS and dysfunction in mice. The present study has investigated the effect of microRNA-200a (miR-200a) on NRF2 signaling and diabetic ED. In aortic endothelial cells (ECs) isolated from C57BL/6 wild-type (WT) mice, high glucose (HG) reduced miR-200a levels and increased the expression of kelch-like ECH-associated protein 1 (Keap1) - a target of miR-200a and a negative regulator of NRF2. This led to the inactivation of NRF2 signaling and exacerbation of OS and inflammation. miR-200a mimic (miR-200a-M) or inhibitor modulated KEAP1/NRF2 antioxidant signaling and manipulated OS and inflammation under HG conditions. These effects were completely abolished by knockdown of Keap1, indicating that Keap1 mRNA is a major target of miR-200a. Moreover, the protective effect of miR-200a-M was completely abrogated in aortic ECs isolated from C57BL/6 Nrf2 knockout (KO) mice, demonstrating that NRF2 is required for miR-200a's actions. In vivo, miR-200a-M inhibited aortic Keap1 expression, activated NRF2 signaling, and attenuated hyperglycemia-induced OS, inflammation and ED in the WT, but not Nrf2 KO, mice. Therefore, the present study has uncovered miR-200a/KEAP1/NRF2 signaling that controls aortic endothelial antioxidant capacity, which protects against diabetic ED.

Citations

• Oxidative Stress and Diabetic Complications

Cited by

• MicroRNA regulation by selenium nanoparticles: Mechanistic insights and translational perspectives in human disease
• Protective role of NRF2 in macrovascular complications of diabetes. [europepmc]
• The Role of microRNAs in Metabolic Syndrome-Related Oxidative Stress. [europepmc]
• Regulation of ferroptosis by non‑coding RNAs in the development and treatment of cancer (Review). [europepmc]
• Nrf2 Signaling Pathway in Chemoprotection and Doxorubicin Resistance: Potential Application in Drug Discovery. [europepmc]
• Inflammatory Mechanisms Contributing to Endothelial Dysfunction. [europepmc]
• Signaling pathways and targeted therapy for myocardial infarction. [europepmc]
• Vaccarin alleviates endothelial inflammatory injury in diabetes by mediating miR-570-3p/HDAC1 pathway. [europepmc]
• Activation of Nrf2 signaling: A key molecular mechanism of protection against cardiovascular diseases by natural products. [europepmc]
• MicroRNAs as Biomarkers for Coronary Artery Disease Related to Type 2 Diabetes Mellitus-From Pathogenesis to Potential Clinical Application. [europepmc]
• The Complex Genetic and Epigenetic Regulation of the Nrf2 Pathways: A Review. [europepmc]
• miR-200a attenuated oxidative stress, inflammation, and apoptosis in dextran sulfate sodium-induced colitis through activation of Nrf2. [europepmc]
• The role of oxidative stress in diabetes mellitus-induced vascular endothelial dysfunction. [europepmc]
• The implication of miR-200a and miR-132 expression and their correlations with NF-κB/TNF-alpha signaling in adults with diabetic nephropathy. [europepmc]
• Role of MicroRNA in linking diabetic retinal neurodegeneration and vascular degeneration. [europepmc]
• Inhibiting miR-200a-3p Increases Sirtuin 1 and Mitigates Kidney Injury in a Tubular Cell Model of Diabetes and Hypertension-Related Renal Damage. [europepmc]

Related

• Long Duration of Type 2 Diabetes Drives Erythrocyte-Induced Vascular Endothelial Dysfunction: A Link to miRNA-210-3p
• Inhibition of miR-181c-5p Rescues Diabetes-Impaired Angiogenesis in Ischemia and Wound Healing
• Long Noncoding RNA MALAT1 and Regulation of the Antioxidant Defense System in Diabetic Retinopathy
• Irisin rescues diabetic cardiac microvascular injury via ERK1/2/Nrf2/HO-1 mediated inhibition of oxidative stress
• Endothelial Nrf2 deficiency promotes atherosclerotic lesion formation by shaping a proinflammatory niche