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

J Mol Cell Cardiol. 2019 Apr;129:105-117. doi: 10.1016/j.yjmcc.2019.02.010. Epub 2019 Feb 18.

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.

Keywords: Angiogenesis; Endothelium; Nitric oxide; Vascular disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Capillary Permeability
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / pathology
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / physiopathology*
  • Gene Deletion
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Hyperglycemia / complications*
  • Hyperglycemia / metabolism*
  • Ischemia / complications*
  • Ischemia / metabolism*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neovascularization, Physiologic
  • Nitric Oxide Synthase Type III / metabolism
  • PTEN Phosphohydrolase / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Transcriptional Activation / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Up-Regulation / genetics
  • Vasodilation

Substances

  • Mdm4 protein, mouse
  • Proto-Oncogene Proteins
  • Tumor Suppressor Protein p53
  • Nitric Oxide Synthase Type III
  • Proto-Oncogene Proteins c-mdm2
  • PTEN Phosphohydrolase