i(3)so3-galactosylceramide and Arteriosclerosis

Scavenger receptors have been proven to be implicated in the formation of atherosclerotic lesions. A series of novel derivatives of sulfatides were synthesized, and their inhibitory activities against incorporation of DiI-acetyl-LDL into macrophages were evaluated in order to clarify the structure-activity relationships of sulfatides as a scavenger receptor inhibitor and find out novel inhibitors with synthetic easiness. The chemical modification of the substructures of sulfatides led to the establishment of the following structure-activity relationships; (1) the ceramide moiety can be replaced with another structure bearing two long chains, (2) the galactose moiety can be replaced with another structure or be deleted without a large decrease in the inhibitory activity, (3) the sulfate moiety was crucial, and it was the most preferable functional group for a potent inhibitory activity. The inhibitory activity of (S)-2-octadecanoylamino-2-tetradecylcarbamoyl)ethyl sulfate sodium salt (3a) against incorporation of DiI-acetyl-LDL into macrophages was proven to be based on the inhibition against the binding of acetyl-LDL to the surface of macrophages. We discovered novel scavenger receptor inhibitors with synthetic easiness, such as (S)-2-octadecanoylamino-2-(tetradecylcarbamoyl)ethyl sulfate sodium salt (3a) and 2-octadecanoylamino-1-(octadecanoylaminomethyl)ethyl sulfate sodium salt (13q).

Topics: Animals; Arteriosclerosis; Dose-Response Relationship, Drug; Iodine Radioisotopes; Lipoproteins, LDL; Macrophages; Membrane Proteins; Mice; Protein Binding; Receptors, Immunologic; Receptors, Lipoprotein; Receptors, Scavenger; Scavenger Receptors, Class B; Structure-Activity Relationship; Sulfoglycosphingolipids

Changes in serum lipids and lipoproteins and progression of atherosclerosis with age were examined in Watanabe heritable hyperlipidemic (WHHL) rabbits with or without treatment with sulfatide. The injection of sulfatide solution caused a reduction of serum triacylglycerols for five months including the period of treatment, but afterwards, failed to lower the level of total cholesterol, triacylglycerols and phospholipids, and to suppress the progression of atherosclerosis. Concentrations of LDL as a major serum lipoprotein in WHHL rabbits with or without the treatment with sulfatide were found to be about 64-fold those of normal rabbits by immunological assay using anti-LDL antiserum, whereas the contents of total cholesterol, triacylglycerols, and phospholipids in WHHL rabbit sera were found to be about 10-fold those of normal rabbits. All WHHL rabbits with or without the treatment with sulfatide contained very small amounts of HDL. Types of apoproteins of isolated LDL and VLDL fractions suggested that the former seemed to be derived from VLDL remnant, and the latter to be derived from chylomicron remnant. It was noted that all WHHL rabbit sera had a significant increased amount of lysophosphatidylcholine, and that the fatty acid composition of total serum lipids had almost no change except for slight decrease in arachidonic acid with age. Pathological examination showed that severe atherosclerotic lesions were not so different between WHHL rabbits with or without treatment with sulfatide at age over 22 months.

Topics: Aging; Animals; Aorta; Arteriosclerosis; Body Weight; Cholesterol; Hyperlipidemias; Lipoproteins; Rabbits; Sulfoglycosphingolipids