Blockade of endothelin receptors markedly reduces atherosclerosis in LDL receptor deficient mice: role of endothelin in macrophage foam cell formation

Objective: We evaluated the direct effects of long-term blockade of ETA and ETB receptors using a mixed endothelin (ET) receptor antagonist, LU224332, in the low density lipoprotein receptor (LDL-R) knockout mouse model of at herosclerosis. Methods: Four groups of LDL-R deficient mice were studied: c ontrol mice fed normal chow (group I); mice fed a high cholesterol (HC, 1.2 5%) diet alone (group II), HC fed animals treated with LU224332 (group UI); and mice fed normal chow treated with the LU compound (group IV). All trea tments were continued for 8 weeks at which time the animals were sacrificed and the aortae were removed and stained with oil red O. Atherosclerotic ar ea (AA) was determined by quantitative morphometry and normalized relative to total aortic area (TA). Results: Cholesterol feeding resulted in a marke d increased in total plasma cholesterol (similar to 15 fold) and widespread aortic atherosclerosis (AA/TA: group I: 0.013+/-0.007; group II: 0.33+/-0. 11; P<0.001). Atherosclerotic lesions were characterized by immunohistochem istry as consisting mainly of macrophages which also showed high levels of ET-1 expression. Treatment with ET antagonist significantly reduced the dev elopment of atherosclerosis (AA/TA: group III: 0.19+/-0.07, P<0.01 vs. grou p II), without altering plasma. cholesterol levels and blood pressure. The direct effect of LU224332 on macrophage activation and foam-cell formation was determined in vitro using a human macrophage cell line, THP-1. Treatmen t of the THP-1 cells with LU224332 significantly reduced cholesterol ester and triacylglycerol accumulation and foam-cell formation on exposure to oxi dized LDL (P<0.01 and P<0.05, respectively). Conclusion: We conclude that a nonselective ET receptor antagonist substantially inhibited the developmen t of atherosclerosis in a genetic model of hyperlipidemia, possibly by inhi biting macrophage foam-cell formation, suggesting a role for these agents i n the treatment and prevention of atherosclerotic vascular disease. (C) 200 0 Elsevier Science B.V. All rights reserved.