Notch pathway activation mediated the senescence of endothelial progenitor cells in hypercholesterolemic mice
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Notch pathway activation mediated the senescence of endothelial progenitor cells in hypercholesterolemic mice Jiawen Liang 1,2 & Xiao Ke 3 & Rongfeng Yang 3 & Xing Wang 1,2 & Zhimin Du 1,2 & Chengheng Hu 1,2 Received: 1 February 2020 / Accepted: 8 September 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
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. Keywords High-fat diet . Cholesterol . Endothelial progenitor cells . Notch pathway . Senescence
Introduction Hyperlipemia (HLP) is the condition of having high levels of low-density lipoprotein (LDL) cholesterol, which can cause metabolic disorder. This condition has been recognized as one of the risk factors of cardiovascular diseases (Karr 2017). Hyperlipidemia can damage the coronary artery, leading to
the deposition of a large amount of lipid proteins in the plasma. In addition, hyperlipidemia impairs the function of endothelial cells, which play an important role in the prevention of cardiovascular diseases (Watanabe et al. 2018). Endothelial progenitor cells (EPCs) derived from the bone marrow are a small population of blood cells, and these cells can differentiate into mature endothelial cells. Therefore, the number and
Jiawen Liang and Xiao Ke contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10863-020-09853-5) contains supplementary material, which is available to authorized users. * Zhimin Du [email protected] * Chengheng Hu [email protected]
Xing Wang [email protected] 1
Jiawen Liang [email protected]
Department of Cardiology, The First Affiliated Hospital,
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