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

Journal of Cellular and Molecular Medicine
Junduo WuHao Wu

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 resc...Continue Reading

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Citations

Jun 27, 2020·International Journal of Molecular Sciences·Estella ZuccoloAngela Raucci
Jul 7, 2020·Journal of Cellular and Molecular Medicine·Junduo WuHao Wu
Jun 20, 2019·International Journal of Molecular Sciences·Celeste CocoMonica Montagnani
Sep 24, 2020·International Journal of Molecular Sciences·Adam WłodarskiAgnieszka Śliwińska
Oct 27, 2021·Cellular and Molecular Life Sciences : CMLS·Angela RaucciEstella Zuccolo

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