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

in Journal of Endocrinology
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  • 1 Department of Hand and Foot Surgery, The First Hospital of Jilin University, Changchun, Jilin, China
  • 2 Department of Cardiology, The Second Hospital of Jilin University
  • 3 Department of Nephrology, The First Hospital of Jilin University, Changchun, Jilin, China
  • 4 Department of Neurosurgery, The Second Hospital of Shandong University, Jinan, Shandong, China
  • 5 Department of Neurology, The Second Hospital of Shandong University, Jinan, Shandong, China
  • 6 Department of Nutrition and Food Hygiene, School of Public Health, Shandong University, Jinan, Shandong, China
  • 7 School of Science and Technology, Georgia Gwinnett College, Lawrenceville, Georgia, USA
  • 8 Department of Acupuncture and Tuina, Changchun University of Chinese Medicine, Changchun, Jilin, China
  • 9 Department of Diabetes Complications and Metabolism, Diabetes Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, California, USA

Correspondence should be addressed to L Lu or H Wu: ljlu@jlu.edu.cn or hwu@sdu.edu.cn
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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.

 

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