Oscillatory shear stress induces the transition of EPCs into mesenchymal cells through ROS/PKCζ/p53 pathway
Autor: | Meiyue Wang, Yu Gao, Min Cheng, Xiaodong Cui, Lanlan Li, Xiaoyun Zhang, Yaowen Zhang, Yanting He, Hong Li |
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Rok vydání: | 2020 |
Předmět: |
Male
0301 basic medicine Time Factors 030226 pharmacology & pharmacy General Biochemistry Genetics and Molecular Biology 03 medical and health sciences 0302 clinical medicine Western blot In vivo medicine Animals General Pharmacology Toxicology and Pharmaceutics Progenitor cell Cells Cultured Protein Kinase C Endothelial Progenitor Cells chemistry.chemical_classification Matrigel Reactive oxygen species medicine.diagnostic_test Chemistry Mesenchymal stem cell Transdifferentiation Thiourea Cell Differentiation Mesenchymal Stem Cells General Medicine Transfection Rats Cell biology 030104 developmental biology Cell Transdifferentiation embryonic structures cardiovascular system Acetanilides Stress Mechanical Tumor Suppressor Protein p53 Reactive Oxygen Species circulatory and respiratory physiology |
Zdroj: | Life Sciences. 253:117728 |
ISSN: | 0024-3205 |
Popis: | Aims Studies indicate that the pattern of shear stress determines the direction of endothelial progenitor cells (EPCs) differentiation. However, the mechanism remains largely unknown. Herein, we try to identify the role of oscillatory shear stress (OSS) in the transdifferentiation of EPCs into mesenchymal cells and the mechanism involved. Materials and methods OSS was applied to EPCs using the flow chamber system in vitro. Matrigel, Boyden chamber, and healing assay were used to observe the changes in EPCs function. Further, 2′,7′-dichlorofluorescein diacetate (DCFH-DA) probe and/or western blot were performed to detect the expression of reactive oxygen species (ROS), p53 and PKCζ in EPCs. EPCs transduced with Lentivirus carrying Tp53 were implanted into the arterial vessel in the balloon injured rat model, and neointimal thickening was verified by HE staining. Key findings OSS enhanced the expression of mesenchymal cell markers alpha-smooth muscle actin (α-SMA) and smooth muscle 22 alpha (SM22α) on EPCs. In the meantime, OSS time-dependently decreased p53 expression in EPCs, which was partially abolished by treatment with ROS scavenger N-acetylcysteine (NAC) or protein kinase C zeta (PKCζ) inhibitor Go6983. Moreover, the p53 agonist tenovin-1 attenuated the changes of OSS-mediated the mesenchymal cell markers and EPCs function. Besides, we also found that transplanting EPCs transfected with LV-Tp53 significantly inhibited neointimal thickening and promoted reendothelialization in vivo. Significance This study demonstrates OSS-induced EPC transdifferentiation into mesenchymal cells and ROS/PKCζ/p53 pathway play an essential role in it. It may serve as a promising therapeutic target for cardiovascular disease in the future. |
Databáze: | OpenAIRE |
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