Skip to Main Content
Frequently Asked Questions
Submit an ETD
Global Search Box
Need Help?
Keyword Search
Participating Institutions
Advanced Search
School Logo
Files
File List
case1270624670.pdf (3.49 MB)
ETD Abstract Container
Abstract Header
Interaction between CD36 and Oxidized LDL Modulates Macrophage Cytoskeletal Functions: A Mechanism of Macrophage Trapping
Author Info
Park, Young Mi
Permalink:
http://rave.ohiolink.edu/etdc/view?acc_num=case1270624670
Abstract Details
Year and Degree
2010, Doctor of Philosophy, Case Western Reserve University, Molecular Biology and Microbiology.
Abstract
Trapping of lipid laden macrophages is a critical but reversible step of arterial and adipose tissue inflammation and contributes to atherosclerosis, obesity and insulin resistance. However, its mechanism is not clearly defined. We tested the hypothesis that CD36, a class B scavenger receptor expressed on macrophages, may be implicated in this process and revealed molecular mechanisms by which oxidized LDL (oxLDL) acts through CD36 and induce macrophage trapping. In vivo and in vitro assays showed that oxLDL but not native LDL inhibited migration of wild type macrophages in a CD36 dependent manner. OxLDL also induced rapid spreading and actin polymerization in CD36 positive, but not negative macrophages. The mechanism was shown to be dependent on oxLDL mediated CD36 signaling which results in sustained activation of focal adhesion kinase (FAK) and inactivation of src homology 2-containing phosphotyrosine phosphatase (SHP-2). The latter was due to generation of reactive oxygen species (ROS) with resulting oxidative inactivation of SHP-2. Macrophage migration in the presence of oxLDL was partially restored by antioxidants or NADPH oxidase inhibitors which restored dynamic activation of FAK. In addition, oxLDL mediated CD36 signaling also induced loss of cell polarity in macrophages. Live cell imaging of macrophages showed that oxLDL, but not native LDL, actuated retraction of macrophage front end lamellipodia. Cd36 null macrophages and macrophages null for Vav, a guanine nucleotide exchange factor (GEF), did not show this effect. Migration velocity and dynamic movement of the macrophage membrane were decreased by oxLDL in a CD36 and Vav dependent manner. These findings were related to the activity of myosin II, a cell polarity determinant. OxLDL induced dephosphorylation of myosin regulatory light chain (MRLC) by increasing the activity of a small molecular weight G protein Rac. Six-thio-GTP which inhibits binding of Vav to Rac, abrogated the effect of oxLDL. Thus, the mechanism causing loss of cell polarity, is via Vav-dependent activation of Rac and dephosphorylation of MRLC. Activation of these pathways may induce trapping of macrophages in the arterial intima and adipose tissue and promote atherosclerosis and diabetic adipose tissue inflammation, two hallmarks of the metabolic syndrome.
Committee
Roy Silverstein, MD (Advisor)
Clifford Harding, MD/PhD (Committee Chair)
Martha Cathcart, PhD (Committee Member)
Paul Fox, PhD (Committee Member)
Pages
152 p.
Subject Headings
Cellular Biology
Keywords
macrophage trapping
;
atherosclerosis
;
CD36
;
scavenger receptor
;
oxidized LDL
Recommended Citations
Refworks
EndNote
RIS
Mendeley
Citations
Park, Y. M. (2010).
Interaction between CD36 and Oxidized LDL Modulates Macrophage Cytoskeletal Functions: A Mechanism of Macrophage Trapping
[Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1270624670
APA Style (7th edition)
Park, Young.
Interaction between CD36 and Oxidized LDL Modulates Macrophage Cytoskeletal Functions: A Mechanism of Macrophage Trapping.
2010. Case Western Reserve University, Doctoral dissertation.
OhioLINK Electronic Theses and Dissertations Center
, http://rave.ohiolink.edu/etdc/view?acc_num=case1270624670.
MLA Style (8th edition)
Park, Young. "Interaction between CD36 and Oxidized LDL Modulates Macrophage Cytoskeletal Functions: A Mechanism of Macrophage Trapping." Doctoral dissertation, Case Western Reserve University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1270624670
Chicago Manual of Style (17th edition)
Abstract Footer
Document number:
case1270624670
Download Count:
968
Copyright Info
© 2010, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.