Function and Distribution of Apolipoprotein A1 in the Artery Wall Are Markedly Distinct From Those in Plasma

被引:92
作者
DiDonato, Joseph A. [1 ]
Huang, Ying [1 ]
Aulak, Kulwant S. [1 ]
Even-Or, Orli [4 ]
Gerstenecker, Gary [1 ,5 ]
Gogonea, Valentin [1 ,5 ]
Wu, Yuping [6 ]
Fox, Paul L. [1 ]
Tang, W. H. Wilson [1 ,2 ]
Plow, Edward F. [3 ]
Smith, Jonathan D. [1 ,2 ]
Fisher, Edward A. [4 ]
Hazen, Stanley L. [1 ,2 ,5 ]
机构
[1] Cleveland Clin, Dept Cellular & Mol Med, Lerner Res Inst, Cleveland, OH 44106 USA
[2] Cleveland Clin, Dept Cardiovasc Med, Inst Heart & Vasc, Cleveland, OH 44106 USA
[3] Cleveland Clin, Dept Mol Cardiol, Lerner Res Inst, Cleveland, OH 44106 USA
[4] NYU, Dept Med, New York, NY 10016 USA
[5] Cleveland State Univ, Dept Chem, Cleveland, OH 44115 USA
[6] Cleveland State Univ, Dept Math, Cleveland, OH 44115 USA
基金
美国国家卫生研究院;
关键词
apolipoproteins; arteriosclerosis; cardiovascular diseases; plaque; atherosclerotic; HIGH-DENSITY-LIPOPROTEIN; ENHANCED CHOLESTEROL EFFLUX; ACUTE CORONARY SYNDROME; PRE-BETA-HDL; ATHEROSCLEROTIC LESIONS; APOA-I; MYELOPEROXIDASE; RETENTION; PARTICLES; CAPACITY;
D O I
10.1161/CIRCULATIONAHA.113.002624
中图分类号
R5 [内科学];
学科分类号
100201 [内科学];
摘要
Background Prior studies show that apolipoprotein A1 (apoA1) recovered from human atherosclerotic lesions is highly oxidized. Ex vivo oxidation of apoA1 or high-density lipoprotein (HDL) cross-links apoA1 and impairs lipid binding, cholesterol efflux, and lecithin-cholesterol acyltransferase activities of the lipoprotein. Remarkably, no studies to date directly quantify either the function or HDL particle distribution of apoA1 recovered from the human artery wall. Methods and Results A monoclonal antibody (10G1.5) was developed that equally recognizes lipid-free and HDL-associated apoA1 in both native and oxidized forms. Examination of homogenates of atherosclerotic plaque-laden aorta showed >100-fold enrichment of apoA1 compared with normal aorta (P<0.001). Surprisingly, buoyant density fractionation revealed that only a minority (<3% of total) of apoA1 recovered from either lesions or normal aorta resides within an HDL-like particle (1.063d1.21). In contrast, the majority (>90%) of apoA1 within aortic tissue (normal and lesions) was recovered within the lipoprotein-depleted fraction (d>1.21). Moreover, both lesion and normal artery wall apoA1 are highly cross-linked (50% to 70% of total), and functional characterization of apoA1 quantitatively recovered from aorta with the use of monoclonal antibody 10G1.5 showed approximate to 80% lower cholesterol efflux activity and approximate to 90% lower lecithin-cholesterol acyltransferase activity relative to circulating apoA1. Conclusions The function and distribution of apoA1 in human aorta are quite distinct from those found in plasma. The lipoprotein is markedly enriched within atherosclerotic plaque, predominantly lipid-poor, not associated with HDL, extensively oxidatively cross-linked, and functionally impaired.
引用
收藏
页码:1644 / 1655
页数:12
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