Initiation of atherosclerotic lesions in cholesterol-fed rabbits. I. Focal increases in arterial LDL concentration precede development of fatty streak lesions.
We have reported that arterial low density lipoprotein (LDL) concentrations and degradation rates in normal rabbits are elevated in those aortic sites most susceptible to early atheromatous lesions resulting from cholesterol feeding. Here we asked whether the focal differences in LDL metabolism observed in normolipidemic rabbits are accentuated during the first 16 days of feeding 2% cholesterol and whether such changes occur before accumulation of significant numbers of macrophage foam cells. No lesions were grossly visible after 16 days of cholesterol feeding. Histology indicated that macrophage foam cells were sparse during this interval and were found only in lesion-prone sites at longer feeding times. We used LDL labeled both with 131I (to trace undegraded LDL), and with the intracellularly trapped ligand 125I-tyramine cellobiose (to trace degraded plus undegraded LDL). The most profound change was a marked and focal increase in the concentration of intact LDL within the arterial wall of lesion-prone sites. After 16 days of cholesterol feeding when the plasma LDL cholesterol concentration had increased 7.6-fold, the concentration of intact LDL in lesion-prone branch sites of the abdominal aorta was increased by 22-fold (from 2.5 to 54 micrograms LDL cholesterol/g). These concentrations were two and 5.7 times, respectively, as great as in the lesion-resistant, nonbranch areas of the abdominal aorta of the same animals. Similar, but less striking, results were found when the lesion-prone aortic arch and intercostal orifices of the thoracic aorta were compared with adjacent lesion-resistant sites. Arterial LDL degradation rates expressed in terms of LDL mass also increased with time of cholesterol feeding, and were greater in the aortic arch and in branch sites of the abdominal aorta than in adjacent lesion-resistant sites. However, fractional rates of degradation of arterial LDL were decreased in all sites by cholesterol feeding, and were lower in susceptible than in resistant sites. This was probably due in large part to saturation and down-regulation of LDL receptors. The timing, focal nature, and site-specificity of these changes suggest that an increased concentration of LDL in the arterial wall may be an early indication of lesion formation and, in fact, may be a necessary first step in the pathogenesis of the fatty streak lesion in cholesterol-fed rabbits.
Schwenke
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Department of Medicine, University of California, San Diego, La Jolla 92093.
Carew
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D000818:Animals; D001158:Arteries / Q000378:metabolism / Q000473:pathology; D001161:Arteriosclerosis / Q000378:metabolism / Q000473:pathology*; D002784:Cholesterol / Q000378:metabolism; D008078:Cholesterol, LDL / Q000378:metabolism; D004036:Diet, Atherogenic; D005487:Foam Cells / Q000378:metabolism; D008074:Lipoproteins / Q000378:metabolism*; D011817:Rabbits; D013997:Time Factors
D008078:Cholesterol, LDL; D008074:Lipoproteins; D002784:Cholesterol