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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:884.)
© 2001 American Heart Association, Inc.

Editorials

Phospholipid Hydrolytic Enzymes in a ‘Cesspool’ of Arterial Intimal Lipoproteins

A Mechanism for Atherogenic Lipid Accumulation

John R. Guyton

From the Departments of Medicine and Pathology, Duke University Medical Center, Durham, NC.

Correspondence to John R. Guyton, MD, Department of Medicine, Duke University Medical Center, Box 3510, Durham, NC 27710. E-mail john.guyton@duke.edu

Key Words: atherosclerosis • phospholipase A₂ • sphingomyelin • low density lipoproteins • fibrous plaque

Most of the lipid in atherosclerotic fibrous plaques is extracellular. How does it get there? Hakala and coworkers¹ describe in this issue of Arteriosclerosis, Thrombosis, and Vascular Biology a pathway involving enzymatic hydrolysis of phospholipids in LDL, leading to lipoprotein aggregation and fusion and hence, to accumulation of lipid droplets. The process is enabled and enhanced in the presence of arterial proteoglycans. This extracellular pathway should be distinguished from the commonly postulated cellular pathway involving uptake of modified LDL in macrophage foam cells, which subsequently die and leave the accumulated lipid in an extracellular location.

Although macrophages and macrophage antigens can be found in the "necrotic," lipid-rich core of plaques, several lines of evidence strongly suggest that most of the lipid derives not from dead foam cells but from the extracellular trapping and processing of LDL.² The evidence can be sketched briefly as follows: (1) The earliest core regions are located deep within the intima of atherosclerotic fatty streaks (in the musculoelastic intimal sublayer) below the level of macrophage foam cells.^{3 4} (2) The lipid core, especially in smaller fibrous plaques, shows a markedly increased ratio of free to esterified cholesterol, whereas the hypothesis of foam cell death would predict more esterified cholesterol.^{3 4 5} (3) The fatty acyl pattern of core cholesteryl esters has more linoleate than oleate, similar to the pattern of plasma lipoproteins, but quite different from the oleate predominance of lesion foam cells.^{4 5} (4) Extracellular lipid droplets in human arterial intima tend to be associated with elastic fibers, are . . . [Full Text of this Article]

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