Abstract
Hyperlipidemia is an important factor in the induction of cardiovascular diseases. However, the molecular mechanisms underlying the vascular injury involved in hyperlipidemia remains unclear. This study aimed to investigate the Notch pathway of endothelial progenitor cells (EPCs) in reendothelialization after vascular injury and to explore the involvement of Notch pathway in the senescence of EPCs. Our results demonstrated that high-fat diet (HFD) treatment inhibited reendothelialization after vascular injury in the mice model. In vitro studies showed that 7-ketocholesterol (7-keto) stimulation induced senescence in the isolated EPCs from mice. In addition, 7-keto markedly upregulated the protein expression of Notch1 and Delta-like ligand 4 and induced the transport of notch intracellular domain (NICD) to the nucleus. Mechanistically, treatment with NICD inhibitor reduced the senescence of the EPCs stimulated by cholesterol. In summary, our results showed that HFD treatment caused the disruption of reendothelialization after vascular injury in the mouse model. In vitro studies indicated that 7-keto-induced senescence of EPCs was at least via the activation of the Notch1 pathway. Mechanistic data suggested that 7-keto may activate the Notch1 pathway by regulating the generation and transport of NICD to the nucleus. Future investigations are warranted to confirm the role of Notch1 in the dysfunction of EPCs during obesity.
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Acknowledgments
The study was supported by Shenzhen Healthcare Research Project (SZBC2017007), Natural Science Foundation of Guangdong Province of China (2016A030313248), Science and Technology project of Guangzhou city of China (201604020129).
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Supplemental Figure S1
Schematic drawings of the in vivo and in vitro experimental procedures. (PNG 666 kb)
Supplementary Figure S2
Effects of 7-keto and DAPT on EPCs viability. The EPCs were stimulated with 7-keto (0, 5,10,20 μM) and then treated with Notch pathway inhibitor, DAPT (10 μM) for 7 days. (A, B) The cytotoxic effects on EPCs were assessed by CCK-8 assay. Both 7-keto and DAPT showed no cytotoxic effects on EPCs. N = 3. (PNG 83 kb)
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Liang, J., Ke, X., Yang, R. et al. Notch pathway activation mediated the senescence of endothelial progenitor cells in hypercholesterolemic mice. J Bioenerg Biomembr 52, 431–440 (2020). https://doi.org/10.1007/s10863-020-09853-5
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DOI: https://doi.org/10.1007/s10863-020-09853-5