Lipoprotein sphingolipids as potential atherogenic factors

From LipidomicsWiki

The accumulation of apolipoprotein B-containing lipoproteins in the intima is one of the first hallmarks of atherosclerosis. Low density lipoproteins are the major carriers of cholesterol in the circulation. Sphingomyelin metabolites are lipoprotein constituents and as such mediate various cell processes which can potentially lead to atherosclerosis. Moreover, sphingomyelinase is secreted by a variety of cells present in atherosclerotic lesions (Marathe et al. 1998, Schissel et al. 1996) and Jiang et al observed a correlation between the plasma concentration of sphingomyelin and severity of coronary heart disease (Jiang et al. 2000). Oxidized low density lipoproteins (ox-LDL) are present in atherosclerotic lesions and their accumulation in macrophages leads to foam cell formation, characteristic for fatty streaks. Analysis of S1P content in oxidized LDL showed reduced levels of S1P and this decrease was associated with a rapid increase in lysophosphatidylcholine (LPC) content (Kimura et al. 2001). Lysophosphatidylcholine is a highly bioactive molecule, which level is greatly elevated in hyperlipidemia, atherosclerotic tissues and ischemic hearts and oxidatively modified LDL are its main source. However, S1P plays also a potential role in thrombus formation and proinflammatory responses to vascular injury and vasoconstriction (Siess et al, 2000). Despite S1P has not been precisely analysed in atherosclerotic lesions, it has been found in LDL particles isolated fom lesions (Murata et al. 2000) and it may be produced locally in the atherosclerotic vessel wall by activated cells (Hobson et al. 2001). Sphingosine-1-phosphate together with other sphingolipids has been found to be produced by cardiac tissue in response to ischemia, hypoxia or reoxygenation (Hernandez et al. 2000). Recent studies suggest that the serum concentration of sphingosine-1-phosphate may be more predictive of obstructive coronary artery disease than traditional risks factors such as serum lipid profiles, hypertension, diabetes mellitus or family history (Deutschman et al. 2003). S1P has been recently found to accumulate in the high density lipoprotein fraction (Murata et al. 2000) and HDL seem to function as carriers for S1P in the circulation. This role has been also suggested for other lipid mediators. The part of ceramide generated de novo is secreted via the VLDL/LDL pathway (Memon et al. 1999) and changes in the activity of hepatic serine-palmitoyl transferase (SPT) affect the rate of ceramide secretion (Merrill et al. 1995). Activation of SPT by palmitic acid leads to the elevation of ceramide in VLDL and LDL. A second mechanism for the regulation of ceramide content in lipoproteins involves the activation of secreted SMase, which hydrolyses sphingomyelin (SM) in LDL to ceramide (Marathe et al. 1998).This enzyme is secreted by vascular endothelial cells and activated macrophages in response to IL-1ß and TNFα in vitro (Marathe et al, 1998) and to LPS in vivo (Wong et al. 2000).
Aggregation of LDL is one of the hallmarks of atherosclerosis (Ross 1990) and it has been documented that aggregated LDL in atherosclerotic lesions is enriched with ceramide (Schissel 1996). Another study by Chatterjee also proved the presence of ceramide in atherosclerotic lesions (Chatterjee 1982). This would confirm the notion that cells in atherosclerotic lesions undergo apoptosis as ceramide is a central messenger in cell death.


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