Inhibition of p53 prevents diabetic cardiomyopathy by preventing early-stage apoptosis and cell senescence, reduced glycolysis, and impaired angiogenesis.
Inhibition of p53 prevents diabetic cardiomyopathy by preventing early-stage apoptosis and cell senescence, reduced glycolysis, and impaired angiogenesis.
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抑制 p53 可通过防止早期细胞凋亡和细胞衰老、糖酵解减少和血管生成受损来预防糖尿病心肌病
DOI：
10.1038/s41419-017-0093-5
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发表时间：
2018-01-23
影响因子：
9
通讯作者：
Cai L
中科院分区：
文献类型：
--
作者：
Gu J;Wang S;Guo H;Tan Y;Liang Y;Feng A;Liu Q;Damodaran C;Zhang Z;Keller BB;Zhang C;Cai L
肿瘤抑制基因P53的表达升高与心脏病有关，包括糖尿病心脏。然而，它在糖尿病心肌病(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P53介导的早期心肌细胞死亡和持续性细胞衰老、糖酵解和血管生成功能障碍。本研究探讨P53蛋白与其特异性抑制剂匹非菊酯-α(PfT-α)联合抑制在扩张型心肌病发病机制中的作用。用多次小剂量链脲佐菌素诱导1型糖尿病模型。高血糖和年龄匹配的对照组小鼠接受和不接受PFT-α治疗，每周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治疗显著阻止了糖尿病引起的心脏重构和功能障碍(即扩张型心肌病)的进展。机制上，在糖尿病早期(0.5月)抑制P53抑制心肌细胞的凋亡，减轻糖尿病引起的细胞衰老(3月和6月)，并在糖尿病后3月和6月通过提高缺氧诱导因子-1α蛋白的稳定性和上调特定靶基因的α转录而改善糖酵解和血管生成缺陷。因此，在糖尿病患者中靶向抑制P53可能为预防DCM提供一种新的途径。
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.
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影响因子：
25.7
作者：
Derdak, Zoltan;Villegas, Kristine A.;Harb, Ragheb;Wu, Annie M.;Sousa, Aryanna;Wands, Jack R.
通讯作者：
Wands, Jack R.
影响因子：
5.6
作者：
Raza H;John A
通讯作者：
John A
影响因子：
20.1
作者：
Natarajan, R;Salloum, FN;Fowler, AA
通讯作者：
Fowler, AA
影响因子：
12.4
作者：
Lall, R.;Ganapathy, S.;Yuan, Z-M
通讯作者：
Yuan, Z-M
影响因子：
8.4
作者：
Gu, Junlian;Wang, Bo;Cai, Lu
通讯作者：
Cai, Lu