Skip to Main Content
 

Global Search Box

 
 
 
 

Files

File List


Yuqi Cui 2014 Dissertation.pdf (4.95 MB)

ETD Abstract Container

Abstract Header

Role of Reactive Oxygen Species in Mediating the Effect of Oxidized Low Density Lipoprotein on Bone Marrow Stem Cells and Endothelial Progenitor Cells in Hyperlipidemia

Cui, Yuqi
http://rave.ohiolink.edu/etdc/view?acc_num=osu1397058562

Abstract Details

2014, Doctor of Philosophy, Ohio State University, Molecular, Cellular and Developmental Biology.
Reactive oxygen species (ROS) are a group of small molecules that regulate tissue redox status and oxidative stress. Redox regulation is an important determinant for cell development, activities, and function. ROS and oxidative stress also have a significant impact on the regulation of stem cells including bone marrow stem cells (BMSCs) and bone marrow-derived endothelial progenitor cells (EPCs). Oxidized low density lipoprotein (ox-LDL), a key contributor to the development of atherosclerosis in hyperlipidemic state, produces a significant amount of ROS spontaneously in vitro at clinically relevant concentrations. The present project was designed to test the hypothesis that ox-LDL was generated from native LDL and altered the populations of stem cells and EPCs via (at least partially) ROS-mediated mechanism. A single dose of human native LDL (25 µg) was injected intravenously into male C57BL/6 mice with and without NAC treatment. Human ox-LDL levels in the blood were measured at different time after LDL injection using ELISA kit. Measurable serum level of human ox-LDL was detected 30 min after the injection, reached peak in 3 hours, started to decline afterwards, and became undetectable in 12 hours. NAC treatment significantly reduced serum ox-LDL level with no detectable ox-LDL in blood 6 hours after injection. No difference in ox-LDL clearance was observed in NAC-treated animals. There were significant increases in intracellular and extracellular ROS production in the animals treated with native LDL and ox-LDL and in hyperlipidemic LDL receptor knockout (LDLR-/-) mice that were completely prevented with NAC treatment. Treatment with ox-LDL significantly altered the populations of stem cells and EPCs in both BM and blood similar to chronic hyperlipidemia (with 4 months of HFD), although significant differences in the impact of ox-LDL and hyperlipidemia on stem/progenitors in vivo exist. Inhibition of ROS production with NAC treatment or expression of a combination of human copper/zinc superoxide dismutase (SOD), extracellular SOD, and cellular glutathione peroxidase (Gpx-1) partially reversed the effect of ox-LDL and hyperlipidemia on the changes in BM and blood stem cell and EPCs. Interestingly, almost all the changes in the mouse blood stem/progenitor cell population by ox-LDL or hyperlipidemia were related to ROS production, while most of BM stem/progenitor cell population changes by ox-LDL or hypherlipedima were independent of ROS generation. Of note, the data appeared to support the concept that intracellular ROS generation might be more important than the extracellular ROS production in mediating the effects of ox-LDL and hyperlipidemia on the BM and blood stem/progenitor cell population, since there was no increase in BM intracellular ROS generation in both ox-LDL-treated animals and hyperlipidemic mice, and the changes in BM cell populations by ox-LDL and hyperlipidemia were largely ROS-independent. NAC treatment also significantly reduced atherosclerotic plaque formation in hyperlipidemic LDLR-/- mice. Clinical study with patients with coronary artery disease and hyperlipidemia showed the number of circulating EPCs was significantly decreased in patients with hyperlipidemia as compared to the healthy individual. Treatment with NAC significantly decreased serum ox-LDL levels in hyperlipidemic patients with no change in LDL level, and significantly increased the number of EPCs in hyperlipidemic patients. In conclusion: Ox-LDL was indeed generated from native LDL in vivo with production of ROS, and significantly interrupted the populations of stem cells and EPCs in the BM and blood similar to chronic hyperlipidemia. ROS-mediated mechanisms especially intracellular ROS formation played a critical role in the actions of ox-LDL and hyperlipidemia on stem/progenitor cells, although ROS-independent mechanisms were also important. Further studies are certainly needed to investigate the mechanisms that are involved in the actions of ox-LDL and hyperlipidemia on individual cell populations.
Zhenguo Liu (Advisor)
Qinghua Sun (Committee Chair)
Loren Wold (Committee Member)
Sampath Parthasarathy (Committee Member)
Xue-Feng Bai (Committee Member)
197 p.
Biochemistry; Biomedical Research; Cellular Biology; Medicine; Pathology
LDL, ox-LDL, hyperlipidemia, NAC, ROS, atherosclerosis, EPC, stem cell

Recommended Citations

Citations

  • Cui, Y. (2014). Role of Reactive Oxygen Species in Mediating the Effect of Oxidized Low Density Lipoprotein on Bone Marrow Stem Cells and Endothelial Progenitor Cells in Hyperlipidemia [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1397058562

    APA Style (7th edition)

  • Cui, Yuqi. Role of Reactive Oxygen Species in Mediating the Effect of Oxidized Low Density Lipoprotein on Bone Marrow Stem Cells and Endothelial Progenitor Cells in Hyperlipidemia. 2014. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1397058562.

    MLA Style (8th edition)

  • Cui, Yuqi. "Role of Reactive Oxygen Species in Mediating the Effect of Oxidized Low Density Lipoprotein on Bone Marrow Stem Cells and Endothelial Progenitor Cells in Hyperlipidemia." Doctoral dissertation, Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1397058562

    Chicago Manual of Style (17th edition)

osu1397058562
96
© 2014, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.