2. Academic Validation
  3. Inhibition of P53/miR-34a improves diabetic endothelial dysfunction via activation of SIRT1

Inhibition of P53/miR-34a improves diabetic endothelial dysfunction via activation of SIRT1

  • J Cell Mol Med. 2019 May;23(5):3538-3548. doi: 10.1111/jcmm.14253.
Junduo Wu 1 2,  Wenzhao Liang 3 4,  Yueli Tian 5,  Fuzhe Ma 6,  Wenlin Huang 7,  Ye Jia 8,  Ziping Jiang 9,  Hao Wu 10
Affiliations

Affiliations

  • 1 Department of Cardiology, The Second Hospital of Jilin University, Changchun, Jilin, China.
  • 2 Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical University, Harbin, Heilongjiang, China.
  • 3 Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China.
  • 4 Occupational and Environmental Medicine Center, Linköping University, Linköping, Sweden.
  • 5 Department of Gastroenteric Medicine, The Second Hospital of Jilin University, Changchun, Jilin, China.
  • 6 Department of Nephrology, The First Hospital of Jilin University, Changchun, Jilin, China.
  • 7 School of Science and Technology, Georgia Gwinnett College, Lawrenceville, Georgia.
  • 8 Department of Diabetes Complications and Metabolism, Diabetes Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, California.
  • 9 Department of Hand and Foot Surgery, The First Hospital of Jilin University, Changchun, Jilin, China.
  • 10 Department of Toxicology and Nutrition, School of Public Health, Shandong University, Jinan, Shandong, China.
PMID: 30793480 DOI: 10.1111/jcmm.14253
Abstract

Endothelial dysfunction contributes to diabetic macrovascular complications, resulting in high mortality. Recent findings demonstrate a pathogenic role of P53 in endothelial dysfunction, encouraging the investigation of the effect of P53 inhibition on diabetic endothelial dysfunction. Thus, high glucose (HG)-treated endothelial cells (ECs) were subjected to pifithrin-α (PFT-α)-a specific inhibitor of P53, or P53-small interfering RNA (siRNA), both of which attenuated the HG-induced endothelial inflammation and oxidative stress. Moreover, inhibition of P53 by PFT-α or P53-siRNA prohibited P53 acetylation, decreased microRNA-34a (miR-34a) level, leading to a dramatic increase in Sirtuin 1 (SIRT1) protein level. Interestingly, the miR-34a inhibitor (miR-34a-I) and PFT-α increased SIRT1 protein level and alleviated the HG-induced endothelial inflammation and oxidative stress to a similar extent; however, these effects of PFT-α were completely abrogated by the miR-34a mimic. In addition, SIRT1 inhibition by EX-527 or Sirt1-siRNA completely abolished miR-34a-I's protection against HG-induced endothelial inflammation and oxidative stress. Furthermore, in the aortas of streptozotocin-induced diabetic mice, both PFT-α and miR-34a-I rescued the inflammation, oxidative stress and endothelial dysfunction caused by hyperglycaemia. Hence, the present study has uncovered a P53/miR-34a/SIRT1 pathway that leads to endothelial dysfunction, suggesting that P53/miR-34a inhibition could be a viable strategy in the management of diabetic macrovascular diseases.

Keywords

P53; aorta; diabetes; endothelial dysfunction; miR-34a.

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