期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 284, 期 45, 页码 30825-30835出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M109.047605
关键词
-
资金
- National Institutes of Health [P01 HL076491-055328, P01 HL077107-050004, P01 HL087018-02001]
- Case Western Reserve University
- Cleveland Clinic Clinical and Translational Science [1KL2RR024990]
High density lipoprotein (HDL) is the major atheroprotective particle in plasma. Recent studies demonstrate that myeloperoxidase (MPO) binds to HDL in vivo, selectively targeting apolipoprotein A1 (apoA1) of HDL for oxidative modification and concurrent loss in cholesterol efflux and lecithin cholesterol acyl transferase activating activities, generating a dysfunctional HDL particle. 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 the loss of modified HDL binding to the HDL receptor, scavenger receptor B1, and concurrent acquisition of saturable and specific 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 levels on aortic endothelial cells exposed to MPO-oxidized HDL. The loss of non-cholesterol efflux activities and the gain of pro-inflammatory functions requires modification of the entire particle and can be recapitulated by oxidation of reconstituted HDL particles comprised of apoA1 and nonoxidizable phosphatidylcholine species. Multiple site-directed mutagenesis studies of apoA1 suggest that the pro-inflammatory activity of MPO-modified HDL does not involve methionine, tyrosine, or tryptophan, oxidant-sensitive residues previously mapped as sites of apoA1 oxidation within human atheroma. Thus, MPO-catalyzed oxidation of HDL results not only in the loss of classic atheroprotective reverse cholesterol transport activities of the lipoprotein but also both the loss of non-cholesterol efflux related activities and the gain of pro-inflammatory functions.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据