Atherosclerosis begins in youth. Fatty streaks and clinically significant raised lesions increase rapidly in prevalence and extent during the 15- to 34-year age span. Primary prevention of atherosclerosis, as contrasted with primary prevention of clinically manifest atherosclerotic disease, must begin in childhood or adolescence.

A quantitative study of the en face size and shape of endothelial cells from aortic intercostal ostia has been carried out in rabbits. Photomicrographs were taken from vascular casts of the rabbit aorta and the endothelial cell outlines were analyzed quantitatively using a digitizer and digital computer. The morphology of the endothelial cells was described using 8 calculated parameters (area, perimeter, length, width, angle of orientation, width: length ratio, axis-intersection ratio and shape index). Marked changes in cell morphology were found in the regions proximal and distal to ostia as well as around flow dividers. Cells on the aorta are aligned with the flow direction, and the endothelial cells within the ostia have an angle of orientation of approximately 45 deg to the axis of the vessel. The results obtained to date suggest that endothelial cell morphology and orientation around a branch vessel may be a natural marker or indicator of the detailed features of blood flow.

Oxidative modification of LDL increases its atherogenicity, and 15-lipoxygenase (15-LO) has been implicated in the process. To address this issue, we generated transgenic rabbits that expressed 15-LO in a macrophage-specific manner and studied their susceptibility to atherosclerosis development when they were fed a high-fat, high-cholesterol (HFHC) diet (Teklad 0533 rabbit diet 7009 with 10% corn oil and 0.25% cholesterol) for 13.5 wk. Transgenic and nontransgenic rabbits developed similar degrees of hypercholesterolemia and had similar levels of triglyceride, VLDL, LDL, and HDL. Quantitative morphometric analysis of the aortic atherosclerosis indicated that the transgenic animals ( n ϭ 19) had significantly smaller lesion areas (9.8 Ϯ 6.5%, mean Ϯ SD) than their littermate controls ( n ϭ 14, 17.8 Ϯ 15.0%) ( P Ͻ 0.05). In a subgroup ( n ϭ 9) of transgenic rabbits that received the HFHC diet plus the antioxidant N Ј , N Ј -diphenyl-phenylenediamine (1%), the extent of lesion involvement (9.8 Ϯ 7.5%) did not differ from the subgroup ( n ϭ 10) that received the regular HFHC diet (9.7 Ϯ 5.9%). Since the results were unexpected, we repeated the experiments. Again, we found that the nontransgenic littermates ( n ϭ 12) had more extensive lesions (11.6 Ϯ 10.6%) than the transgenic rabbits ( n ϭ 13; 9.5 Ϯ 7.8%), although the difference was not significant. In a third set of experiments, we crossed 15-LO transgenic rabbits with Watanabe heritable hyperlipidemic (WHHL) rabbits and found that the lesion area in the 15-LO transgenic/heterozygous WHHL rabbits ( n ϭ 14) was only about one third (7.7 Ϯ 5.7%) that found in nontransgenic heterozygous WHHL littermate controls ( n ϭ 11, 20.7 Ϯ 19.4%) ( P Ͻ 0.05). These data suggest that overexpression of 15-LO in monocytes/macrophages protects against lipid deposition in the vessel wall during early atherogenesis in these rabbit models of atherosclerosis. ( J. Clin

Lecithin:cholesterol acyltransferase (LCAT) is a key plasma enzyme in cholesterol and high density lipoprotein (HDL) metabolism. Transgenic rabbits overexpressing human LCAT had 15-fold greater plasma LCAT activity than nontransgenic control rabbits. This degree of overexpression was associated with a 6.7-fold increase in the plasma HDL cholesterol concentration in LCAT transgenic rabbits. On a 0.3% cholesterol diet, the HDL cholesterol concentrations increased from 24 ± 1 to 39 + 3 mg/dl in nontransgenic control rabbits (n = 10; P < 0.05) and increased from 161 + 5 to 200 ± 21 mg/dl (P < 0.001) in the LCAT transgenic rabbits (n = 9). Although the baseline non-HDL concentrations of control (4 ± 3 mg/dl) and transgenic rabbits (18 ± 4 mg/dl) were similar, the cholesterol-rich diet raised the non-HDL cholesterol concentrations, reflecting the atherogenic very low density, intermediate density, and low density lipoprotein particles observed by gel filtration chromatography. The non-HDL cholesterol rose to 509 + 57 mg/dl in controls compared with only 196 ± 14 mg/dl in the LCAT transgenic rabbits (P < 0.005). The differences in the plasma lipoprotein response to a cholesterol-rich diet observed in the transgenic rabbits paralleled the susceptibility to developing aortic atherosclerosis. Compared with nontransgenic controls, LCAT transgenic rabbits were protected from diet-induced atherosclerosis with significant reductions determined by both quantitative planimetry (-86%; P < 0.003) and quantitative immunohistochemistry (-93%; P < 0.009). Our results establish the importance of LCAT in the metabolism of both HDL and apolipoprotein B-containing lipoprotein particles with cholesterol feeding and the response to diet-induced atherosclerosis. In addition, these findings identify LCAT as a new target for therapy to prevent atherosclerosis.