Molecular Pathology in Atherosclerosis: The Mechanism How Cholesteryl Ester Accumulates in Atheromatous Aorta

Abstract

To study how cholesterol accumulates in atheroma, novel monoclonal antibodies were developed, using crude homogenate of atheroma as immunogens. 212D monoclonal antibody recognizing extra cellular matrix with lipid-laden deposits was selected by histochemical staining. The antigen was deduced vitronectin from cDNA library. DLH3 monoclonal antibody recognizing oxidized LDL, epitope of which was 5-or 9-phosphatidylcholine. Signiˆcant correlations between oxidized LDL and coronary heart disease (CHD) patients were observed from clinical study. 256C monoclonal antibody recognizing atheromatous lesions in human aorta was selected. Epitope must be PC-cholesterol complex which may involve in foam cell rupture. Atherogenesis will be discussed from the aspects of these antibodies. Our working hypothesis is required to elucidate the mechanism. Denatured lipoproteins (either oxidized lipoprotein or ruptured foam cells) may induce atheroma. Oxidation of lipoprotein may be taken place both in foam cells and/or extra cellular matrix, and macrophage eliminate these denatured lipoproteins and become foam cells. The foam cells are ruptured by either apoptosis or necrosis afterward, and hydrophobic fragments of foam cells dispersed in extra cellular space, which destroys the function of biological membrane. Since biological function could be maintained by segregation of hydrophilic circumstances, macrophages uptake these fragmented material and oxidized lipoprotein to maintain the function. This vicious spiral may enhance chronically the atheroma.

Detection of Vulnerable Coronary Plaques by Color Fluorescent Angioscopy

“…During plaque growth, collagen I is replaced by collagen III, IV, and/or V (8 -10), and CFs are degenerated, disrupted, and finally destroyed by matrix metalloproteinases released by macrophages (11). During this process, macrophages accumulate lipids such as cholesteryl esters (CEs) and Ox-LDL (12,13) and become foam cells while simultaneously producing ceramide within themselves (14); their death results in formation of the lipid core (15). Therefore, demonstrating the lack of collagen I, which is mainly contained in normal CFs, deposition of lipids, and existence of Ox-LDL, suggests the likelihood of vulnerable plaques, but in vivo clinical tools to visualize them in the coronary plaques are lacking.…”

Levels of sCD40 Ligand in Chronic and Acute Coronary Syndromes and its Relation to Angiographic Extent of Coronary Arterial Narrowing

“…Macrophages are found in plaques of all stages and may transform into lipidladen ''foam cells'' that constitute much of the atheromatous core. 27,28 Macrophages and T-cell lymphocytes are critical in the growth and change of plaques through the secretion of growth factors such as platelet-derived growth factor, which stimulate smooth muscle proliferation and extracellular matrix secretion, cytokines such as interferon-g and IL-1, and extracellular matrix digesting enzymes such as metalloproteinases, which weaken fibrous caps. 29 The current study demonstrates that the serum levels of sCD40L were significantly higher in patients with UA and MI compared with SA patients and controls.…”

Histological Characteristics of Glistening Yellow Coronary Plaques Seen on Angioscopy - With Special Reference to Vulnerable Plaques -

“…4 Ceramide is a marker of macrophage and foam cells. 5 This substance was stained purple by Ziel-Neelsen staining. It was difficult to differentiate between the macrophages and foam cells because both contain ceramide.…”

“…2, 3 During plaque growth, collagen I inside and outside the CF is replaced by III, IV or V, the CF degenerate and are disrupted, and then finally are destroyed by matrix metalloproteinases released from macrophages. 4 During this process, macrophages accumulate lipids such as cholesteryl esters and oxidized low-density lipoprotein 5 and become foam cells while simultaneously producing ceramide within themselves; 6 their death results in formation of the necrotic core (NC) 7 followed by calcium deposition.…”