HDL consists of heterogeneous lipoproteins and plays an important role for antiatherogenic function. HDL can be clarified either by its apolipoprotein composition: Lp A-I containing apo A-I but no apo A-II and Lp A-I/A-II containing both apo A-I and apo A-II, or by its particle size:large sized HDL₂ and small sized HDL₃. Recent studies have indicated that specific HDL subclasses may be responsible for antiatherogenic properties.
To confirm antiatherogenic HDL subclasses independendent of HDL cholesterol levels, we investigated the relationship between HDL subclasses and angiographically documented coronary artery disease (CAD) in 125 patients with a predominance of small LDL, which has been recognized as atherogenic state with dyslipidemia of low HDL cholesterol and high triglycerides.
Patients with diabetes mellitus or who were taking lipid-lowering drugs were excluded. CAD(+) was defined as ≥50% stenosis in major coronary arteries. Lp A-I particles was quantified as the concentration of apo A-I in these particles by using a differential electroimmunoassay with hydrated agarose gels containing monospecific antibodies against apo A-I and apo A-II.
HDL₂ were examined by 4∼30% nondenaturing polyacrylamide gradient gel electrophoresis and the percentage of HDL2 protein (%HDL₂) of the total HDL protein on densitometric scan area were determined.
The CAD(+) group (n=82) had older patients (p=0.02) and higher proportion of male (p=0.01) compared with CAD(-) group (n=43). Although both groups had high levels of triglycerides and low levels of HDL cholesterol and apo A-I, there were no significant differences between the two groups.
Analysis of HDL subclasses revealed that Lp A-I levels were significant lower in CAD(+) than in CAD(-) (37.5±11.4mg/dl vs. 54.2±13.4mg/dl, p<0.0001) and %HDL₂ were also lower in CAD(+) than in CAD(-) (17%vs. 26%, p=0.08).
CAD(+) frequency was lowest in highest quartiles of Lp A-I levels (23%) and it was inversely associated with Lp A-I levels (p<0.001).
HDL cholesterol and Lp A-I were not associated with triglycerides, however, %HDL₂ exhibited a significant correlation with triglycerides (r=0.56, p=0.046).
These findings indicate that Lp A-I and HDL₂ levels represent a protective effect of HDL subclasses independent of HDL cholesterol levels in individuals with a predominance of small LDL.
We conclude that HDL metabolism producing largesized HDL containing only apo A-I may be important for antiatherogenic function.

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Oxidatively modified LDL is thought to be involved in atherogenesis, since it promotes foam cell formation from macrophages. A variety of receptors against oxidized LDL including scavenger receptor (SR-A type I and II) have been discovered. The study of oxidized LDL metabolism from the view point of receptors has been progressing rapidly. On the other hand, the nature of oxidized LDL, namely modified structures, mechanism of LDL oxidation, metabolic fate, however, has not been yet understood. Upon oxidatin of LDL with copperion, many types of reactions, such as peroxidation of lipids, modification of apolipoprotein B, physical changes in LDL particles, proceed in an uncontroled manner. Thus, oxidized LDL is a mixture of heterogenously modified lipoprotein particles. Isolation of oxidized LDL from plasma or atherosclerotic lesions and its quantitation have not been done until recently. We raised a monoclonal antibody against oxidized LDL as an approach to investigate its modified structure and to analyze its metabolism quantitatively. Our antioxidized LDL monoclonal antibody, DLH3, stained foam cells in human atherosclerotic lesions immunohistochemically. By a new sensitve method of measuring oxidized LDL in human plasma LDL fractions using DLH3, we found that the oxidation level of plasma LDL from patients of vascular diseases, hemodialysis, and familial LCAT deficiency was significantly higher that that of normal subjects.

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Rupture of the atherosclerotic plaque is closely related to thrombus formation and subsequent ischemic disease, such as acute coronary syndrome. However, the mechanism of thrombus formation after plaque rupture is not well understood. We examined the immnohistochemical localization of tissue factor (TF) in the human atherosclrotic lesion with monoclonal antibody against human TF. We also examined TF activity in the atherosclerotic intima that is experimentally induced by cholesterol feeding in rabbits, and in the coculture system of human umbilical vein endothelial cells (HUVEC) and human peripheral blood monocytes (PBMC) which are stimulated by oxidized LDL. TF was mainly localized in the foam cells, most of which are derived from macrophages, and its localization is well correlated with that of fibrin. Less amount of TF was also seen in the extracellular matrix. Experimentally induced atherosclerotic intima showed TF activity more intensely than non-atherosclerotic intima. The TF activity was thought to be derived from subendothelial tissue which was full of foamy macrophages, as scanning electron microscopy demonstrated exposure of subendothelial tissue. In vitro studies revealed that oxidized LDL stimulated TF activity in coculture of HUVEC and PBMC and that this stimulation required direct contact between the two cells. These findings suggest that TF localizing in atherosclerotic intima plays an important role not only in fibrin formation within atherosclerotic plaque but also in thrombus formation at the rupture site of plaque.

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