Pivotal mechanisms involved in atherogenesis include.
1. Focal intimal influx and accumulation of plasma lipoproteins at lesion—prone sites.
2. Focal intimal monocyte—macrophage recruitment.
3. Generation within the intima of reactive oxygen species of free radicals by smooth muscle cells, macrophages and endothelial cells.
4. Oxidative modification of intimal lipoproteins by these reactive oxygen species to produce such oxidatively modified lipoproteins species as oxidized LDL and Lp(a).
5. Foam cell formation due to the uptake of oxidatively modified lipoproteins by the non—down—regulating macrophage scavenger receptors.
6. Foam cell necrosis, most likely due to the cytotoxic effects of oxidatively modified LDL. This process gives rise to the extracellular lipid core, and is an important event in the transition from the reversible fatty streak to the less readily reversible, more advanced atherosclerotic lesion.
7. Smooth muscle cell migration to and proliferation in the arterial intima, a process in which platelet—derived growth factor is believed to act as a chemo oattractant. Fibroblast growth factors likely regulate smooth muscle cell proliferation.
8. Plaque rupture, primarily at sites of greatest macrophage density. Proteolytic enzymes released by macrophages may stimulate plaque rupture, which ultimately leads to mural or occlusive thrombosis. Thrombosis contributes significantly to the stages of plaque growth.
9. Autoimmune inflammation, likely the result of anti—genic epitopes of oxidized LDL. Lipoproteins, such as LDL and Lp(a), enter the subendothelial space and intercept free radicals generated by endothelial cells. Following oxidation, these charge—modified lipoproteins are taken up by the non—down—regulating macrophage scavenger receptors pathway, resulting in lipid—rich, cho—lesteryl ester rich foam cells. Concurrently, circulating monocytes continue to attach to the endothelium, attracted by the chem oattractant MCP–1, and oxidized LDL. The expression and synthesis of MCP–1 by endothelial and smooth muscle cells is augmented by oxidatively modified lipoproteins, allowing the process to continue.
The next phase in atherogenesis is the development of the classic fatty streak as result of the continued uptake of oxidatively modified LDL by the macrophage scavenger receptors with continuing foam cell formation. A few smooth muscle cells can also be seen apparently entering the subendothelial space and proliferating within the intima during this phase. The transitional phase of atherogenesis is characterized by necrosis of the foam cells and the formation of an extracellular lipid core. In this stage, there is an increase in both smooth muscle cells proliferation and collagen synthesis, and lesions continue to grow. As long as elevated low density lipoproteins are present in the circulation, the atherosclerosis process continues. Among the additional changes taking place is the influx of Tlymphocytes. The involvenment of an autoimmune inflammatory component becomes obvious in the late stages of lesion development and is reflected by a prominent lymphocytic infiltration of the adventitia.
atherogenesis – атерогенез
plaque – атеросклеротическая бляшка
lymphocytic – лимфотический
inflammatory – воспалительный
low density lipoproteins – липопротеины низкой плотности