desmosine and Hypercholesterolemia

We tried to develop an experimental model using mice for the primary screening of antiatherosclerotic agents. Male ICR strain mice were given a high-cholesterol diet supplemented with 10% linoleic acid for 14 weeks. Throughout the experimental period, weight gain of these mice was significantly inhibited as compared to that of control mice given a basal diet, but displayed a steady increase comparable to that of the high-cholesterol diet without linoleic acid. The cholesterol and linoleic acid-fed mice showed increased serum cholesterol and phospholipid levels, and decreased serum triglyceride and high-density lipoprotein-(HDL) cholesterol levels and lecithin/cholesterol acyltransferase (LCAT) activity, as well as a markedly increased lipid peroxide level which was a characteristic appearance in the serum of this mouse model. At the end of the experiment, uniform and significant increases in cholesterol, notably cholesteryl ester, were observed in the aorta. Also found were marked decreases in the aorta contents of desmosine and isodesmosine, which are cross-linking amino acids present only in the elastin. Histological observations showed accumulations of fatty droplets in the intima. These changes were much less in mice receiving a high-cholesterol diet without linoleic acid. In this mouse model, probucol prevented elevation of serum cholesterol, phospholipid, and cholesterol accumulation in the aorta. Increases in lipid peroxide level and decreases in LCAT activity were also prevented. These findings indicate that this mouse model is useful for primary screening of antiatherosclerotic agents with antioxidative activity.

Topics: Animals; Anticholesteremic Agents; Aorta; Arteriosclerosis; Cholesterol; Cholesterol, Dietary; Desmosine; Disease Models, Animal; Drug Evaluation, Preclinical; Hypercholesterolemia; Linoleic Acid; Linoleic Acids; Lipid Peroxides; Lipids; Male; Mice; Mice, Inbred ICR; Phosphatidylcholine-Sterol O-Acyltransferase; Probucol

The turnover and degradation of mature elastin from the aortae of Japanese quail were estimated following injection with L-[U-14C]lysine by measuring the changes in specific activity of L-[U-14C]lysine and 14C-labelled desmosine and isodesmosine (crosslinking amino acids derived from lysyl residues) in elastin over a 39-week period. Only 5% of the variation in radioactivity could be attributed to changes in time. Therefore, it was concluded that the best estimates of mature elastin turnover are only quantifiable in years. Dietary cholesterol in amounts sufficient to induce plaque formatioin and fragmentation of the elastic lamina in the aorta did not significantly influence turnover time. It would appear that once the total pool of elastin in aorta is stabilized as mature fibers it is not subject to proteolysis or resynthesis of sufficient magnitude to result in measurable turnover.

Topics: Animals; Aorta; Carbon Radioisotopes; Cholesterol, Dietary; Coturnix; Desmosine; Elastin; Female; Hypercholesterolemia; Lysine; Male