P53 plays a crucial role in endothelial dysfunction associated with hyperglycemia and ischemia. (April 2019)

• Record Type: Journal Article
• Authors: Yokoyama, Masataka; Shimizu, Ippei; Nagasawa, Ayako; Yoshida, Yohko; Katsuumi, Goro; Wakasugi, Takayuki; Hayashi, Yuka; Ikegami, Ryutaro; Suda, Masayoshi; Ota, Yusuke; Okada, Sho; Fruttiger, Marcus; Kobayashi, Yoshio; Tsuchida, Masanori; Kubota, Yoshiaki; Minamino, Tohru
• Is Part Of: Journal of molecular and cellular cardiology. Volume 129(2019)
• Page Start: 105
• Page End: 117
• Publication Date: 2019-04
• Subjects: Endothelium -- Nitric oxide -- Angiogenesis -- Vascular disease; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2019.02.010
• Languages: English
• ISSNs: 0022-2828

Abstract

Graphical abstract: Image 2 Abstract: 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 loss-of-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. Highlights: Endothelial p53 negatively regulates eNOS phosphorylation and impairs endothelium-dependent vasodilatation. p53-induced inhibition of eNOS is mediated by PTEN transactivation, contributing to diabetic endothelial dysfunction. Inhibition of endothelial p53 activation enhances ischemia-induced angiogenesis. Overexpression of p53 by Mdm2/Mdm4 deletion impairs endothelial function.