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    Mitochondrial Reactive Oxygen Species Mediate Lysophosphatidylcholine-induced Endothelial Cell Activation

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    Genre
    Thesis/Dissertation
    Date
    2015
    Author
    Li, Xinyuan
    Advisor
    Yang, Xiao-Feng
    Committee member
    Wang, Hong, 1956 September 19-
    Ashby, Barrie
    Tilley, Douglas G.
    Muniswamy, Madesh
    Sheu, Shey-Shing
    Department
    Pharmacology
    Subject
    Pharmacology
    Immunology
    Cellular Biology
    Atherosclerosis
    Endothelial Cell
    Inflammation
    Lysophosphatidylcholine
    Mitochondria
    Reactive Oxygen Species
    Permanent link to this record
    http://hdl.handle.net/20.500.12613/3191
    
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    DOI
    http://dx.doi.org/10.34944/dspace/3173
    Abstract
    Lysophosphatidylcholines (LPCs) are a class of pro-inflammatory lipids that play important roles in atherogenesis. LPC activates endothelial cells (ECs) to upregulate adhesion molecules, cytokines and chemokines, which is the initiation step of atherogenesis. However, the mechanisms underlying LPC-triggered EC activation are not fully understood. Previously considered as the toxic by-products of cellular metabolism, mitochondrial reactive oxygen species (mtROS) are recently found to directly contribute to both the innate and adaptive immune responses. Here we tested a novel hypothesis that mtROS serve as signaling mediators for LPC-induced EC activation. Using electron spin resonance and flow cytometry with mtROS-specific fluorescence probe MitoSOX, we found that several LPC species including LPC 16:0, 18:0, and 18:1 induced mtROS in human primary aortic ECs (HAECs). Mechanistically, our analysis using confocal microscopy and Seahorse XF96 mitochondrial function analyzer showed that LPC induced mtROS via increasing mitochondrial calcium-mediated increase of mitochondrial respiration. In addition, we found that mtROS scavenger MitoTEMPO abolished LPC-induced EC activation by downregulating Intercellular adhesion molecule 1 (ICAM-1) in HAECs. Moreover, our analysis with mass spectrometer analysis of histone H3 lysine acetylation and electrophoretic mobility shift assay (EMSA) showed that MitoTEMPO acts by blocking LPC-induced histone H3 lysine 14 acetylation (H3K14ac) and nuclear translocation of pro-inflammatory transcription factor activator protein-1 (AP-1). Remarkably, all the above effects can be inhibited by anti-inflammatory cytokines interleukin (IL-35) and IL-10. Our results indicate that mtROS are responsible for LPC-induced EC activation, which can be inhibited by anti-inflammatory cytokines. MtROS targeting therapies and anti-inflammatory cytokines such as IL-35 may serve as novel therapeutic targets for vascular inflammation and cardiovascular diseases. The studies in this dissertation were supported by grants from the National Institutes of Health (NIH) funded to Dr. Xiao-Feng Yang.
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