Development of the atherosclerotic core region. Chemical and ultrastructural analysis of microdissected atherosclerotic lesions from human aorta.

Abstract

Lipid deposits in human atherosclerotic fibrous plaques exhibit marked differences in chemistry and ultrastructure from lipid deposits in fatty streaks, leading some investigators to question whether fibrous plaques originate from fatty streaks. To examine lesion transition, we employed lipid microanalysis, electron microscopy, and immunohistochemistry on fatty streaks, fibrolipid lesions (small raised lesions), and fibrous plaques from human aorta. Both fatty streaks and caps of fibrolipid lesions were high in esterified cholesterol content (mean, 62% of total cholesterol) and high in cholesteryl oleate content compared with cholesteryl linoleate content. Fatty streaks and fibrolipid lesion caps also showed similar morphology, characterized mostly by macrophage-derived foam cells in the superficial intima. Core lipids in both small and large raised lesions differed markedly from this pattern. Fibrolipid lesion cores showed mostly vesicular extracellular deposits, sometimes accompanied by cholesterol L ipid deposition in human arterial fatty streaks consists mostly of cholesteryl esters, of which cholesteryl oleate is the most prominent, occurring primarily in cytoplasmic lipid droplets with droplet profile diameters generally exceeding 0.4 /xm. Lipid deposits in large, mature fibrous plaques, in contrast, are often enriched in free cholesterol, have cholesteryl linoleate as the most prominent cholesteryl ester, and are found predominantly in the extracellular space in the form of small lipid droplets (less than 0.4 pm profile diameter) and vesicles. 16 These discrepant features have provided the impetus to question (1) whether the fibrous plaque core originates from lipids accumulated in foam cells via death of the cells and (2) whether fibrous plaque lesions have their origin in preexisting fatty streaks.Human fibrous plaque core lipids may primarily originate from direct deposition of lipoprotein lipids in the extracellular space rather than from dead foam cells. 6This suggestion is based on observations of the site of lipid deposits in the smallest detectable core regions, the small sizes of lipid particles in core regions, cholesteryl ester fatty acyl patterns, binding of lipoproteins to the extracellular matrix, and the demonstration of lipoprotein fusion. 1 -513 However, no previous studies, including our own, have examined in detail the chemis-

Glycation of low-density lipoproteins by methylglyoxal and glycolaldehyde gives rise to the in vitro formation of lipid-laden cells

“…45% using 100 mmol/l, and 34% for 10 mmol/l. These values are similar to those detected in human atherosclerotic lesions [49].…”

Hydrazine compounds inhibit glycation of low-density lipoproteins and prevent the in vitro formation of model foam cells from glycolaldehyde-modified low-density lipoproteins

“…No significant changes in lipid composition (triglyceride, phospholipid, cholesterol and cholesteryl esters) or the lipid:protein ratio were detected (B. E. Brown and M. J. Davies, unpublished data). These glycated LDL are recognised by scavenger receptors (other than the LDL receptor) on J774A.1 murine macrophages [29] and primary human monocyte-derived macrophages (B. E. Brown, I. Rashid, D. M. van Reyk and M. J. Davies, unpublished data) giving rise to intracellular accumulation of cholesterol and cholesterol esters. Such lipid-laden cells are models of the foam cells that play a critical role in the development and progression of atherosclerosis.…”

Apolipoprotein B in Cholesterol-Containing Drusen and Basal Deposits of Human Eyes with Age-Related Maculopathy

“…It will be interesting to determine whether sub-RPE deposits exhibit a progression in the physical forms of cholesterol like the atherosclerotic intima. Maturation of the lipid-rich core is associated with pooling of EC, aggregation of UC-rich liposomes, and formation of UC crystals 19,43,44 that together contribute to plaque instability. 25 Neither we nor others have observed cholesterol crystals in sub-RPE deposits.…”