PubMed · 5428992
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A Lemaire. 1970-07-04. [Hyperlipemia].. https://pubmed.ncbi.nlm.nih.gov/5428992/
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Combined treatment with trypsin, cholesterol esterase, and neuraminidase transforms LDL, but not HDL or VLDL, to particles with properties akin to those of lipid extracted from atherosclerotic lesions. Single or double enzyme modifications, or treatment with phospholipase C, or simple vortexing are ineffective. Triple enzyme treatment disrupts the ordered and uniform structure of LDL particles, and gives rise to the formation of inhomogeneous lipid droplets 10-200 nm in diameter with a pronounced net negative charge, but lacking significant amounts of oxidized lipid. Enzymatically modified LDL (E-LDL), but not oxidatively modified LDL (ox-LDL), is endowed with potent complement-activating capacity. As previously found for lipid isolated from atherosclerotic lesions, complement activation occurs to completion via the alternative pathway and is independent of antibody. E-LDL is rapidly taken up by human macrophages to an extent exceeding the uptake of acetylated LDL (ac-LDL) or oxidatively modified LDL. After 16 h, cholesteryl oleate ester formation induced by E-LDL (50 micrograms/ml cholesterol) was in the range of 6-10 nmol/mg protein compared with 3-6 nmol/mg induced by an equivalent amount of acetylated LDL. At this concentration, E-LDL was essentially devoid of direct cytotoxic effects. Competition experiments indicated that uptake of E-LDL was mediated in part by ox-LDL receptor(s). Thus, approximately 90% of 125I-ox-LDL degradation was inhibited by a 2-fold excess of unlabeled E-LDL. Uptake of 125I-LDL was not inhibited by E-LDL. We hypothesize that extracellular enzymatic modification may represent an important step linking subendothelial deposition of LDL to the initiation of atherosclerosis.
Atherosclerosis and its consequences account for most morbidity and mortality in Western countries. Atherosclerosis develops over a period of decades and has a complex pathogenesis. It is a disease of the intima and primarily involves four cell types, i.e. endothelial and vascular smooth muscle cells, monocytes and platelets. In recent years, elucidation of the cellular and molecular mechanisms of these cells, and their alterations by cardiovascular risk factors and in atherosclerosis, has markedly expanded knowledge of this disease. In particular, it became clear that endothelial cells play a crucial role in the regulation of platelet function and coagulation, as well as vascular tone and structure. Interestingly, endothelial dysfunction occurs early on in the presence of cardiovascular risk factors such as hyperlipidemia, hypertension and diabetes. This could lead to adhesion of circulating platelets and monocytes, increased accumulation of lipids in the subintima, increased contraction, migration and proliferation of vascular smooth muscle cells. The fact that atherosclerosis develops only in some but not in other parts of the circulation, however, has rarely been considered. With the development of molecular biology it has now become possible to clone differentially expressed genes in vessels with or without atherosclerosis; this in turn makes it possible to characterize better the molecular and cellular mechanisms of the disease. The search for such candidate genes could form the basis for future genetic interventions. This therapeutic approach is likely to assume clinical importance, particularly in monogenetic diseases (i.e. familial hypercholesteremia), while its use in complex polygenetic diseases such as atherosclerosis is more difficult. Restenosis, however, may be accessible to gene therapy earlier on as it is accessible to local gene transfection.
Finding that an avian herpesvirus can cause atherosclerosis in chickens prompted studies of human herpesviruses in human atherosclerosis. Antigens and nucleic acid sequences of cytomegalovirus (CMV), a widespread member of the herpesvirus family, were found in arterial lesions in human atherosclerosis, but infectious virus has not been observed. In atherosclerosis patients, high levels of CMV antibodies are present, suggesting the presence of virus that had been activated from a latent state. Atherosclerosis also develops in immune-suppressed heart transplant patients infected with CMV. The properties of CMV are consistent with its involvement at several levels of the atherogenic process. If this concept is correct, immunization with a CMV vaccine should prevent CMV infection and atherosclerosis.