Atherosclerotic lesions in the common coronary arteries of ApoE knockout mice.

OBJECTIVE: The present study describes the distribution of atherosclerotic lesions in the coronary arteries of chow-fed 60-week-old male ApoE(-/-), 17-beta-estradiol-treated ApoE(-/-), and wild-type mice. METHODS AND RESULTS: The histologic examination of coronary arteries in 12 ApoE(-/-) and 6 wild-type mice, in contrast to the distribution of atherosclerosis in human coronary arteries, reveals that the major lesions in the mouse are located in the valve sinus, including the origins of the coronary arteries. These retrovalvular lesions either stop abruptly at the orifice of the common coronary artery or extend a short distance onto the arterial trunks. The first segment and first branch of all the major coronary arteries, the usual sites of disease in humans, are protected from disease. Although the arterial trunks and the first level branches are free of disease, we found approximately four independent lesions per heart. Independent lesions are present in the heart in smaller, intramyocardial vessels. These lesions are comprised predominantly of macrophages and proteoglycan and exhibit little extracellular lipid. In some cases, the independent lesions occlude the lumen without evidence of myocardial infarct in the surrounding tissue. CONCLUSIONS: The specificity of the localization of lesions in certain segments of the murine coronary tree suggests that fundamental properties found at different branch levels determine lesion location.

Estrogen inhibits the initiation of fatty streaks throughout the vasculature but does not inhibit intra-plaque hemorrhage and the progression of established lesions in apolipoprotein E deficient mice.

Estrogen has previously been shown to inhibit development of early atherosclerotic lesions in hyperlipidemic mice. However, it is still not known whether estrogen also inhibits progression and destabilization of lesions once established and whether there are other effects of long-term hormone therapy in mice. To address this question, male, 20-week old, apolipoprotein E deficient mice were administered 17-beta estradiol or placebo subcutaneously for between 4 and 40 weeks. Estrogen administration did not cause regression of established lesions in the carotid arteries, aortic arch and thoracic aorta but prevented the initiation of new lesions in the abdominal aorta and iliac, femoral and popliteal arteries. Although the established lesions were slightly smaller in the innominate artery of the estrogen treated mice, estrogen did not prevent lesion progression. Estrogen administration also had no effect on the frequency of intra-plaque hemorrhage, atrophy of the fibrous cap, medial erosion, and fibro-fatty nodules, but did reduce the frequency of fatty streaks that form on top of or adjacent to the established lesions in the innominate artery. These data suggest that estrogen inhibits the initiation of the fatty streak but does not alter the progression of established lesions through stages of instability and healing.

Aggressive very low-density lipoprotein (VLDL) and LDL lowering by gene transfer of the VLDL receptor combined with a low-fat diet regimen induces regression and reduces macrophage content in advanced atherosclerotic lesions in LDL receptor-deficient mice.

Very low-density lipoprotein (VLDL) and LDL plasma levels are associated with cardiovascular mortality. Whereas VLDL/LDL lowering causes regression of early atherosclerotic lesions, less is known about the effects of aggressive lipid lowering on regression of advanced complex lesions. We therefore investigated the effect of VLDL/LDL lowering on pre-existing lesions in LDL receptor-deficient mice. Mice fed a high-fat diet for 16 weeks developed advanced lesions with fibrous caps, necrotic cores, and cholesterol clefts in the brachiocephalic artery. After an additional 14 weeks on a low-fat diet, plasma cholesterol levels decreased from 21.0 +/- 2.6 to 8.4 +/- 0.6 mmol/L, but lesions did not regress. Levels of VLDL/LDL were further lowered by using a helper-dependent adenovirus encoding the VLDL receptor (HD-Ad-VLDLR) under control of a liver-selective promoter. Treatment with HD-Ad-VLDLR together with a low-fat diet regimen resulted in reduced lesion size (cross-sectional area decreased from 146,272 +/- 19,359 to 91,557 +/- 15,738 microm2) and an 89% reduction in the cross-sectional lesion area occupied by macrophages compared to controls. These results show that aggressive VLDL/LDL lowering achieved by hepatic overexpression of VLDLR combined with a low-fat diet regimen induces regression of advanced plaques in the brachiocephalic artery of LDL receptor-deficient mice.