Cell death in atherosclerosis
Sammanfattning: Rupture of atherosclerotic lesions is recognized as the major cause of acute cerebrovascular and coronary syndromes. The characteristics of the typical vulnerable plaque include increased inflammatory cells at the shoulder region, a large lipid core, a thin fibrous cap with few collagen fibers and smooth muscle cells. The release of proteolytic enzymes produced by macrophages, generation of cytokines by T cells and death of smooth muscle cells in lesions may contribute to plaque instability. Oxidation of LDL in the vessel wall renders the LDL particles proinflammatory and cytotxic. However, the type of cell death occurring in vivo and the factors responsible for its' induction have remained equivocal. Cholesterol homeostasis is achieved through regulation of the uptake, synthesis and esterification of cholesterol. It has been recently shown that extrahepatic cells such as macrophages can eliminate intracellular cholesterol by enzymatic conversion into 27-hydroxycholesterol and 3ß-hydroxy-5-cholestenoic acid. The sterol 27-hydroxylase is the enzyme responsible for the conversion of cholesterol to 27-oxygenated products. The introduction of statins, as potent inhibitors of HMG-CoA reductase has resulted in significant decrease in cardiovascular morbidity and mortality. Angiographic assessment has shown that improvement in arterial topographical morphology occurs slowly and only to a small extent (1-2%). These observations have led to the concept of plaque stabilisation, as a new strategy for prevention of acute cardiovascular syndromes. Advanced human carotid atherosclerotic plaques were characterized by a high frequency of degenerating smooth muscle cells with ongoing DNA fragmentation. The presence of DNA ladder suggested that some of these cells undergo apoptotic cell death, but electron microscopic analysis indicated that most dying cells in the plaque were in a state of oncosis. Analysis of the relation between DNA framentation and plaque cell composition demonstrated a significant association between degree of TUNEL positivity and T cell infiltration. High serum LDL cholesterol levels were associated with increased macrophage staining in atherosclerotic lesions. Degenerating cells were almost exclusively found in or very close to regions with strong oxidized LDL inummoreactivity. Exposure of smooth muscle cells to oxidized LDL induced cell death of a similar pattern found in atherosclerotic lesions. Sterol 27-hydroxylase functions as a defence towards accumulation of cholesterol in macrophages by enzymatic conversion of intracellular cholesterol into 27-hydroxycholesterol and 3ß-hydroxy-5-cholestenoic acid. We found the sterol 27-hydroxylase immunoreactivity to be located primarily to macrophages and endothelial cells in humans atherosclerotic lesions. In humans, the sterol 27-hydroxylase mechanism is more active compared to other species such as the rabbit. A substantially lower amount of lipids, particularly oxidized LDL, T cells and macrophages and degenerating cells were observed in atherosclerotic lesions obtained from patients with advanced carotid artery stenosis treated with pravastatin for 3 months prior to carotid endarterectomy. The present findings support the hypothesis that oxidized LDL is highly toxic towards vascular smooth muscle cells and induces oncosis, a pattern found in dying smooth muscle cells and other cells in advanced human carotid plaques. Moreover, they indicate that pravastatin treatment may stabilise the plaque composition by reducing oxidized LDL, inflammation and number of degenerating cell in vivo in humans.
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