ENHANCED REDUCTION OF ATHEROSCLEROSIS IN HAMSTERS TREATED WITH PRAVASTATIN AND CAPTOPRIL - ACE IN ATHEROMAS PROVIDES CELLULAR TARGETS FOR CAPTOPRIL

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductas e and angiotensin-converting enzyme (ACE) reduce experimental atherosc lerosis by different mechanisms. To determine whether dual-drug therap y additively retards the progression of early lesions, control hyperli pidemic hamsters were compared with those treated with pravastatin, ca ptopril, and pravastatin plus captopril. After 8 weeks of treatment, p ravastatin (34 mg/kg/day) reduced plasma total cholesterol and triglyc erides by 41 and 84%, respectively, whereas captopril (100 mg/kg/day) reduced normal blood pressure by 21%. The combination of pravastatin a nd captopril (33 and 100 mg/kg/day) decreased plasma total cholesterol and triglycerides by 44 and 84%, and blood pressure was decreased by 14%. In the aortic arch, pravastatin reduced macrophage-foam cell size and fatty streak area by 21 and 31%, respectively, whereas captopril decreased macrophage-foam cell number and fatty streak area by 34 and 35%. Pravastatin plus captopril decreased macrophage-foam cell number, foam cell size, and fatty streak area by 38, 24, and 67%. ACE inhibit ors were previously reported to retard atherosclerosis without affecti ng blood pressure, suggesting that these agents acted on the artery wa ll. Therefore the expression of arterial ACE was determined in normal and atherosclerotic hamster aortas. ACE messenger RNA (mRNA) and prote in were detected in endothelial cells, intimal macrophage-foam cells a nd medial smooth-muscle cells of atherosclerotic arteries indicating a n upregulation of ACE expression with hyperlipidemia and atheroscleros is. In conclusion, dual-therapy with pravastatin and captopril produce d an additive reduction in fatty streak area compared with either drug alone and suggested that atherogenesis can be retarded beyond the lev el achieved with monotherapy. The presence of ACE in endothelial cells and intimal macrophage-foam cells provides cellular targets for capto pril to directly modify the formation of early atherosclerotic lesions .