2. Academic Validation
  3. Sodium butyrate attenuates diabetes-induced aortic endothelial dysfunction via P300-mediated transcriptional activation of Nrf2

Sodium butyrate attenuates diabetes-induced aortic endothelial dysfunction via P300-mediated transcriptional activation of Nrf2

  • Free Radic Biol Med. 2018 Aug 20;124:454-465. doi: 10.1016/j.freeradbiomed.2018.06.034.
Junduo Wu 1,  Ziping Jiang 2,  Haina Zhang 3,  Wenzhao Liang 4,  Wenlin Huang 5,  Huan Zhang 6,  Ying Li 7,  Zhaohui Wang 8,  Junnan Wang 1,  Ye Jia 9,  Bin Liu 10,  Hao Wu 11
Affiliations

Affiliations

  • 1 Department of Cardiology, The Second Hospital of Jilin University, 218 Ziqiang St., Changchun, Jilin 130041, People's Republic of China.
  • 2 Department of Hand and Foot Surgery, The First Hospital of Jilin University, 71 Xinmin St, Changchun, Jilin 130021, People's Republic of China.
  • 3 Department of Rehabilitation, The Second Hospital of Jilin University, 218 Ziqiang St., Changchun, Jilin 130041, People's Republic of China.
  • 4 Department of Neurology, China-Japan Union Hospital of Jilin University, 126 Xiantai St, Changchun, Jilin 130033, People's Republic of China.
  • 5 School of Science and Technology, Georgia Gwinnett College, Lawrenceville, GA 30043, USA.
  • 6 Operating Theatre, China-Japan Union Hospital of Jilin University, 126 Xiantai St, Changchun, Jilin 130033, People's Republic of China.
  • 7 Department of Dermatology, Affiliated Hospital of Beihua University, 12 Jiefang Rd., Jilin, Jilin 132000, People's Republic of China.
  • 8 Department of Acupuncture and Tuina, Changchun University of Chinese Medicine, 1035 Boshuo Rd, Changchun, Jilin 130117, People's Republic of China.
  • 9 Department of Nephrology, The First Hospital of Jilin University, 71 Xinmin St., Changchun, Jilin 130021, People's Republic of China.
  • 10 Department of Cardiology, The Second Hospital of Jilin University, 218 Ziqiang St., Changchun, Jilin 130041, People's Republic of China. Electronic address: [email protected].
  • 11 Department of Hand and Foot Surgery, The First Hospital of Jilin University, 71 Xinmin St, Changchun, Jilin 130021, People's Republic of China; Department of Translational Medicine, The First Hospital of Jilin University, 71 Xinmin St., Changchun, Jilin 130021, People's Republic of China. Electronic address: [email protected].
PMID: 29964168 DOI: 10.1016/j.freeradbiomed.2018.06.034
Abstract

Oxidative stress and inflammation are major contributors to diabetes-induced endothelial dysfunction which is the critical first step to the development of diabetic macrovascular complications. Nuclear factor erythroid 2-related factor 2 (NRF2) plays a key role in combating diabetes-induced oxidative stress and inflammation. Sodium butyrate (NaB) is an inhibitor of histone deacetylase (HDAC) and an activator of NRF2. However, NaB's effect on diabetes-induced aortic injury was unknown. It was also not known whether or to what extent NRF2 is required for both self-defense and NaB's protection in the diabetic aorta. Additionally, the mechanism by which NaB activates NRF2 was unclear. Therefore, C57BL/6 Nrf2 knockout (KO) and wild type (WT) mice were induced to diabetes by streptozotocin, and were treated in the presence or absence of NaB, for 20 weeks. The KO diabetic mice developed more severe aortic endothelial oxidative stress, inflammation and dysfunction, as compared with the WT diabetic mice. NaB significantly attenuated these effects in the WT, but not the KO, mice. In high glucose-treated aortic endothelial cells, NaB elevated Nrf2 mRNA and protein without facilitating NRF2 nuclear translocation, an effect distinct from that of sulforaphane. NaB inhibited HDAC activity, and increased occupancy of the transcription factor Aryl Hydrocarbon Receptor and the co-activator P300 at the Nrf2 gene promoter. Further, the P300 inhibitor C646 completely abolished NaB's efficacies. Thus, NRF2 is required for both self-defense and NaB's protection against diabetes-induced aortic endothelial dysfunction. Other findings suggest that P300 mediates the transcriptional activation of Nrf2 by NaB.

Keywords

Aorta; Diabetes; Endothelial dysfunction; Inflammation; Oxidative stress.

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