p53 plays a crucial role in endothelial dysfunction associated with hyperglycemia and ischemia

Masataka Yokoyama, Ippei Shimizu, Ayako Nagasawa, Yohko Yoshida, Goro Katsuumi, Takayuki Wakasugi, Yuka Hayashi, Ryutaro Ikegami, Masayoshi Suda, Yusuke Ota, Sho Okada, Marcus Fruttiger, Yoshio Kobayashi, Masanori Tsuchida, Yoshiaki Kubota, Tohru Minamino

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)105-117
Number of pages13
JournalJournal of Molecular and Cellular Cardiology
Volume129
DOIs
Publication statusPublished - 2019 Apr 1

Keywords

  • Angiogenesis
  • Endothelium
  • Nitric oxide
  • Vascular disease

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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  • Cite this

    Yokoyama, M., Shimizu, I., Nagasawa, A., Yoshida, Y., Katsuumi, G., Wakasugi, T., Hayashi, Y., Ikegami, R., Suda, M., Ota, Y., Okada, S., Fruttiger, M., Kobayashi, Y., Tsuchida, M., Kubota, Y., & Minamino, T. (2019). p53 plays a crucial role in endothelial dysfunction associated with hyperglycemia and ischemia. Journal of Molecular and Cellular Cardiology, 129, 105-117. https://doi.org/10.1016/j.yjmcc.2019.02.010