Department of Cardiology, The Second Hospital of Jilin University, Changchun, Jilin, China.
Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical University, Harbin, Heilongjiang, China.
J Cell Mol Med. 2019 May;23(5):3538-3548. doi: 10.1111/jcmm.14253. Epub 2019 Feb 22.
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.
内皮功能障碍导致糖尿病大血管并发症，导致高死亡率。最近的研究结果表明，P53 在血管内皮功能障碍中起致病作用，这鼓励了研究 P53 抑制对糖尿病血管内皮功能障碍的影响。因此，用高葡萄糖（HG）处理的内皮细胞（EC）用 pifithrin-α（PFT-α）——一种 P53 的特异性抑制剂，或 P53 小干扰 RNA（siRNA）进行处理，这两种方法都减轻了 HG 诱导的内皮炎症和氧化应激。此外，PFT-α 或 P53-siRNA 抑制 P53 乙酰化，降低 microRNA-34a（miR-34a）水平，导致 SIRT1 蛋白水平显著增加。有趣的是，miR-34a 抑制剂（miR-34a-I）和 PFT-α 增加了 SIRT1 蛋白水平，并以相似的程度缓解了 HG 诱导的内皮炎症和氧化应激；然而，PFT-α 的这些作用完全被 miR-34a 模拟物所消除。此外，SIRT1 抑制通过 EX-527 或 Sirt1-siRNA 完全消除了 miR-34a-I 对 HG 诱导的内皮炎症和氧化应激的保护作用。此外，在链脲佐菌素诱导的糖尿病小鼠的主动脉中，PFT-α 和 miR-34a-I 均挽救了高血糖引起的炎症、氧化应激和内皮功能障碍。因此，本研究揭示了导致内皮功能障碍的 P53/miR-34a/SIRT1 途径，表明 P53/miR-34a 抑制可能是治疗糖尿病大血管疾病的可行策略。
