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Role of Myeloperoxidase Mediated Oxidative Modification and Apolipoprotein Composition in High Density Lipoprotein Function

Undurti, Arundhati

Abstract Details

2010, Doctor of Philosophy, Case Western Reserve University, Cell Biology.
High levels of high density lipoprotein (HDL) are associated with a decreased risk of cardiovascular disease (CVD). The atheroprotective function of HDL has been attributed to its key role in the reverse cholesterol transport (RCT) pathway. However, recent evidence suggests that HDL can be rendered “dysfunctional”, impairing its ability to promote RCT. The work described here suggests two mechanisms that can render HDL “dysfunctional.” The first mechanism involves oxidation of HDL by the enzyme myeloperoxidase (MPO). Recent studies demonstrate that MPO binds to HDL in vivo, selectively targeting HDL for oxidative modification. We now show that (patho) physiologically relevant levels of MPO-catalyzed oxidation result in loss of non cholesterol efflux activities of HDL including anti-apoptotic and anti-inflammatory functions. One mechanism responsible is shown to involve loss of oxidized HDL binding to the HDL receptor, scavenger receptor B1, and concurrent acquisition of binding to a novel unknown receptor independent of scavenger receptors CD36 and SR-A1. HDL modification by MPO is further shown to confer pro-inflammatory gain of function activities as monitored by NF-kappa B activation and surface vascular cell adhesion molecule (VCAM-1) levels on aortic endothelial cells. Multiple site-directed mutagenesis studies of HDL suggest that the pro-inflammatory activity does not involve methionine, tyrosine, or tryptophan residues—oxidant sensitive residues previously mapped as sites of oxidation within human atheroma. A second mechanism for generating dysfunctional HDL involves changing the apolipoprotein composition. Apolipoprotein A2 (apoA2) is the second most abundant protein in HDL. However, the role of apoA2 in the atheroprotective function of HDL is not well defined. We now show that apoA2 containing HDL is less anti-apoptotic and less anti-inflammatory than HDL containing only apoA1. Further, oxidation of apoA2 containing HDL by MPO generates a particle that has increased pro-inflammatory gain of function activity. Additionally, mice transgenic for mouse apoA2 have lower levels of macrophage RCT compared to wild type controls. Further analysis demonstrates that the rate of cholesterol delivery to the liver is impaired in apoA2 transgenic mice. Taken together, the findings described in this thesis support the idea that the quality of HDL is as important as quantity preventing CVD
Stanley Hazen (Advisor)
Alan Levine (Committee Chair)
Jonathan Smith (Committee Member)
Menachem Shoham (Committee Member)
Mark Chance (Committee Member)
191 p.

Recommended Citations

Citations

  • Undurti, A. (2010). Role of Myeloperoxidase Mediated Oxidative Modification and Apolipoprotein Composition in High Density Lipoprotein Function [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1279209478

    APA Style (7th edition)

  • Undurti, Arundhati. Role of Myeloperoxidase Mediated Oxidative Modification and Apolipoprotein Composition in High Density Lipoprotein Function. 2010. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1279209478.

    MLA Style (8th edition)

  • Undurti, Arundhati. "Role of Myeloperoxidase Mediated Oxidative Modification and Apolipoprotein Composition in High Density Lipoprotein Function." Doctoral dissertation, Case Western Reserve University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1279209478

    Chicago Manual of Style (17th edition)