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
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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