XII^th International Symposium on Atherosclerosis, Stockholm, Sweden. (June 25-29, 2000)
Drugs that shift the structure and composition of the lipoprotein away from an atherogenic profile reduce the in vitro affinity of apoB100 lipoproteins for matrix proteoglycans. These approaches could be used in the control of LDL atherogenicity within the intima of the vessel walls.

Stockholm, Sweden -- Dr G. Camejo (Wallenberg Laboratory, Goteborg, Sweden) overviewed the role of extracellular matrix in atherosclerosis.

Low density lipoproteins and extracellular matrix The discussion was limited to those aspects of the interaction between apoB-100 lipoproteins and the matrix that appear to be modulators of the atherogenicity of these lipoproteins. In terms of volume, not weight, the major components of the intima of large arteries are the proteoglycans (PGs). They form a tridimensional network that fills approximately 60% of the space between the endothelial cells and the internal elastic lamina. The normal intima, and regions prone to lesion development, is initially rich in large versican-like PGs. These are the most abundant PGs of the intimal extracellular space and have chondroitin sulfate (CS) as GAGs. The content of CS-PGs increases with lesion progression and eventually decreases in advanced lesions. Versican-like PGs because of their abundance and affinity with apoB-100 lipoproteins, are most likely the main structure of the intima interacting with particles that reach this space. Other PGs that are less abundant than versican can also form complexes with LDL. Decorin, a small PG containing a single dermatan sulfate chain that interconnects and organizes collagen I and III fibers in the intima, is a prominent component of the fibrous cap. The pericellular heparan-containing PGs, such as the large perlecan and the small syndecan and glypican, are anchored to the plasma membrane. They form a layer that completely surrounds endothelial and smooth muscle cells. Lipoprotein lipase, associated with the cell surface PGs, appears to contribute to the association between apoB-100 lipoproteins and pericellular heparan and CS-PGs, probably through the formation of ternary complex. The association with PGs and GAGs introduces an irreversible alteration of the particle surface. ApoB-100 becomes noticeably more susceptible to tryptic hydrolysis, suggesting that lysine- and arginine-rich regions become more exposed. There is ample evidence that hydrolytic modifications of the LDL lipids take place in the intima.

Phospholipase A2 and LDL in the matrix. sPLA2 has a high affinity for versican-like PG from human arterial smooth muscle cells. A ternary complex PG-LDL-sPLA2 appears to potentiate the activity of the enzyme on LDL. The products of the sPLA2 action are lysolecithin and fatty acids. Lysolecithin is a potent mitogen in vascular cells, which also augments the expression of cell-adhesion molecules in the endothelium and limits the nitric oxide-mediated relaxation in arteries. Another enzyme that may be an important modifier of LDL in the extracellular matrix, also with cellular consequences, is sphyngomyelinase. This enzyme induces rapid aggregation of LDL and generates ceramide, a lipid messenger that has potent cell actions. Another interesting possibility is that the reversible associations of LDL with proteoglycans and GAGs in the intima could extend residence time required for the slow oxidative modifications of LDL. In summary, four of the modification processes that may contribute to the atherogenicity of LDL in the intima (aggregation and lipid phase segregation, proteolytic degradation of the apoB-100, hydrolysis of phospholipids and free radical-mediated oxidation of its unsaturated fatty acids) are enhanced after association with PGs and GAGs. In the intima, essentially irreversible associations of LDL with PGs exist and the resident macrophages may also internalise them. This uptake causes a significant accumulation of cholesterol and its esters in the cell. This could be an important contributor to their transformation into foam cells in lesions.

Modulation of LDL-PGs interaction by pharmacological intervention. Gemfibrozil as well as fenofibrate and simvastatin administered to hypertensive patients with high incidence of dyslipidemia cause a significant decrease of the LDL-PG reactivity. Thus drugs that shift the structure and composition of the lipoprotein away from an atherogenic profile reduce the in vitro affinity of apoB100 lipoproteins for matrix proteoglycans. These studies provide additional support for the validity of these approaches in the control of LDL atherogenicity within the intima of the vessel walls.