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Journal of Lipid Research, Vol. 46, 389-403, March 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Thematic Review

Thematic review series: The Immune System and Atherogenesis. Lipoprotein-associated inflammatory proteins: markers or mediators of cardiovascular disease?

Alan Chait¹, Chang Yeop Han, John F. Oram and Jay W. Heinecke

Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington, Seattle, WA 98195

¹ To whom correspondence should be addressed. e-mail: achait{at}u.washington.edu

In humans, a chronically increased circulating level of C-reactive protein (CRP), a positive acute-phase reactant, is an independent risk factor for cardiovascular disease. This observation has led to considerable interest in the role of inflammatory proteins in atherosclerosis. In this review, after discussing CRP, we focus on the potential role in the pathogenesis of human vascular disease of inflammation-induced proteins that are carried by lipoproteins. Serum amyloid A (SAA) is transported predominantly on HDL, and levels of this protein increase markedly during acute and chronic inflammation in both animals and humans. Increased SAA levels predict the risk of cardiovascular disease in humans. Recent animal studies support the proposal that SAA plays a role in atherogenesis. Evidence is accruing that secretory phospholipase A₂, an HDL-associated protein, and platelet-activating factor acetylhydrolase, a protein associated predominantly with LDL in humans and HDL in mice, might also play roles both as markers and mediators of human atherosclerosis. In contrast to positive acute-phase proteins, which increase in abundance during inflammation, negative acute-phase proteins have received less attention. Apolipoprotein A-I (apoA-I), the major apolipoprotein of HDL, decreases during inflammation. Recent studies also indicate that HDL is oxidized by myeloperoxidase in patients with established atherosclerosis. These alterations may limit the ability of apoA-I to participate in reverse cholesterol transport. Paraoxonase-1 (PON1), another HDL-associated protein, also decreases during inflammation. PON1 is atheroprotective in animal models of hypercholesterolemia. Controversy over its utility as a marker of human atherosclerosis may reflect the fact that enzyme activity rather than blood level (or genotype) is the major determinant of cardiovascular risk. Thus, multiple lipoprotein-associated proteins that change in concentration during acute and chronic inflammation may serve as markers of cardiovascular disease.

In future studies, it will be important to determine whether these proteins play a causal role in atherogenesis.

Supplementary key words inflammation • C-reactive protein • serum amyloid A • apolipoprotein A-I • high density lipoprotein • paraoxonase-1 • secretory phospholipase A₂ • platelet-activating factor acetylhydrolase • myeloperoxidase

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