p53 plays a crucial role in endothelial dysfunction associated with hyperglycemia and ischemia
p53 plays a crucial role in endothelial dysfunction associated with hyperglycemia and ischemia
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DOI：
10.1016/j.yjmcc.2019.02.010
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发表时间：
2019-04-01
影响因子：
5
通讯作者：
Minamino, Tohru
中科院分区：
文献类型：
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作者：
Yokoyama, Masataka;Shimizu, Ippei;Minamino, Tohru
p53是基因组的守护者，保护免受致癌作用。越来越多的证据表明，p53随着年龄的增长而激活。据报道，这种激活有助于各种年龄相关的病理，但其在血管功能障碍中的作用在很大程度上是未知的。本研究的目的是探讨是否激活内皮细胞p53有病理影响的内皮功能。我们通过分别用floxed Trp 53或floxed Mdm 2/Mdm 4小鼠饲养内皮细胞特异性Cre小鼠，建立内皮细胞p53功能丧失和功能获得模型。然后注射链脲佐菌素诱发糖尿病。在糖尿病状态下，内皮细胞p53表达明显上调，内皮依赖性血管舒张功能明显受损。内皮细胞p53基因敲除（EC-p53 KO）小鼠血管舒张功能的损害显著改善，内皮细胞p53基因的缺失也显著增强了缺血诱导的血管生成。相反，通过删除Mdm 2/Mdm 4激活内皮p53减少内皮依赖性血管舒张和缺血诱导的血管生成。将p53引入人内皮细胞上调了磷酸酶和张力蛋白同源物（PTEN）的表达，从而降低了磷酸化eNOS水平。与这些结果一致，内皮p53缺失对内皮功能的有益影响在eNOS缺陷背景的EC-p53 KO小鼠中减弱。这些结果表明，内皮p53负调控内皮依赖性血管舒张和缺血诱导的血管生成，这表明，抑制内皮p53可能是一个新的治疗目标，在代谢紊乱患者。
p53 is a guardian of the genome that protects against carcinogenesis. There is accumulating evidence that p53 is activated with aging. Such activation has been reported to contribute to various age-associated pathologies, but its role in vascular dysfunction is largely unknown. The aim of this study was to investigate whether activation of endothelial p53 has a pathological effect in relation to endothelial function. We established endothelial p53 lossof-function and gain-of-function models by breeding endothelial-cell specific Cre mice with floxed Trp53 or floxed Mdm2/Mdm4 mice, respectively. Then we induced diabetes by injection of streptozotocin. In the diabetic state, endothelial p53 expression was markedly up-regulated and endothelium-dependent vasodilatation was significantly impaired. Impairment of vasodilatation was significantly ameliorated in endothelial p53 knockout (EC-p53 KO) mice, and deletion of endothelial p53 also significantly enhanced the induction of angiogenesis by ischemia. Conversely, activation of endothelial p53 by deleting Mdm2/Mdm4 reduced both endothelium-dependent vasodilatation and ischemia-induced angiogenesis. Introduction of p53 into human endothelial cells up-regulated the expression of phosphatase and tensin homolog (PTEN), thereby reducing phospho-eNOS levels. Consistent with these results, the beneficial impact of endothelial p53 deletion on endothelial function was attenuated in EC-p53 KO mice with an eNOS-deficient background. These results show that endothelial p53 negatively regulates endothelium-dependent vasodilatation and ischemia-induced angiogenesis, suggesting that inhibition of endothelial p53 could be a novel therapeutic target in patients with metabolic disorders.