Ruian Center of Chinese-American Research Institute for Diabetic Complications, the Third Affiliated Hospital of the Wenzhou Medical University, Ruian, China.
Chinese-American Research Institute for Diabetic Complications, the School of Pharmaceutical Sciences of the Wenzhou Medical University, Wenzhou, China.
Cell Death Dis. 2018 Jan 23;9(2):82. doi: 10.1038/s41419-017-0093-5.
Elevated tumor suppressor p53 expression has been associated with heart diseases, including the diabetic heart. However, its precise role in the pathogenesis of diabetic cardiomyopathy (DCM) remains unclear. We hypothesized that the development of DCM is attributed to up-regulated p53-mediated both early cardiac cell death and persistent cell senescence, glycolytic and angiogenetic dysfunctions. The present study investigated the effect of p53 inhibition with its specific inhibitor pifithrin-α (PFT-α) on the pathogenesis of DCM and its associated mechanisms. Type 1 diabetes was induced with multiple low doses of streptozotocin. Both hyperglycemic and age-matched control mice were treated with and without PFT-α five times a week for 2 months and then sacrificed at 3 and 6 months post-diabetes. Treatment with PFT-α significantly prevented the progression of diabetes-induced cardiac remodeling and dysfunction (i.e., DCM). Mechanistically, the inhibition of p53 prevented the cardiac apoptosis during early-stage diabetes (0.5 month), attenuated diabetes-induced cell senescence (3 and 6 months), and improved both glycolytic and angiogenic defects by increasing hypoxia-induced factor (HIF)-1α protein stability and upregulating HIF-1α transcription of specific target genes at 3 and 6 months after diabetes. Therefore, the targeted inhibition of p53 in diabetic individuals may provide a novel approach for the prevention of DCM.
肿瘤抑制因子 p53 表达水平升高与心脏病有关，包括糖尿病性心脏病。然而，其在糖尿病性心肌病（DCM）发病机制中的确切作用仍不清楚。我们假设 DCM 的发展归因于上调的 p53 介导的早期心脏细胞死亡和持续的细胞衰老、糖酵解和血管生成功能障碍。本研究探讨了 p53 特异性抑制剂 pifithrin-α（PFT-α）对 DCM 发病机制及其相关机制的影响。采用多次小剂量链脲佐菌素诱导 1 型糖尿病。高血糖和年龄匹配的对照组小鼠每周用 PFT-α 治疗 5 次，持续 2 个月，然后在糖尿病后 3 个月和 6 个月处死。PFT-α 的治疗显著阻止了糖尿病引起的心脏重构和功能障碍（即 DCM）的进展。从机制上讲，p53 的抑制作用可防止早期糖尿病（0.5 个月）中的心脏凋亡，减轻糖尿病引起的细胞衰老（3 个月和 6 个月），并通过增加缺氧诱导因子（HIF）-1α 蛋白稳定性和上调 HIF-1α 在糖尿病后 3 个月和 6 个月时的特定靶基因转录来改善糖酵解和血管生成缺陷。因此，糖尿病个体中 p53 的靶向抑制可能为预防 DCM 提供一种新方法。
