Bocan T M, Mueller S B, Brown E Q, Lee P, Bocan M J, Rea T, Pape M E
Department of Vascular and Cardiac Diseases, Parke-Davis Pharmaceutical Research, Division of Warner Lambert Company, Ann Arbor, MI 48105, USA.
Atherosclerosis. 1998 Jul;139(1):21-30. doi: 10.1016/s0021-9150(98)00046-x.
Given the beneficial effects of HMG-CoA reductase and ACAT inhibitors on hypercholesterolemia and atherosclerosis, we hypothesized that coadministration would improve the hypolipidemic response and not only limit lesion development but also alter the cellular composition of atherosclerotic lesions so as to induce a stable atherosclerotic lesion morphology. Plasma total cholesterol exposure was reduced 29 and 39% with atorvastatin (2.5 mg/kg) and CI-976 (5 mg/kg), respectively, and 60% upon coadministration due primarily to reductions in VLDL-cholesterol. Modest changes in liver cholesterol ester (CE) content were observed with atorvastatin or CI-976; however, a striking 48% reduction was noted upon coadministration. Liver HMG-CoA reductase mRNA levels were reduced 73% by cholesterol feeding and drug treatment did not prevent the reduction; however, atorvastatin alone and upon coadministration blunted the decrease in LDL receptor mRNA levels. The CE content of the iliac-femoral was unaffected by atorvastatin but was reduced 35% by CI-976 and 53% upon coadministration. Thoracic aortic CE content was reduced 38% by atorvastatin, 48% by CI-976 and 80% upon coadministration. Iliac-femoral lesion and macrophage area were reduced 48 and 67% by atorvastatin, respectively, and 68 and 81% by CI-976 but upon coadministration only an 85% reduction in macrophage area was noted. Aortic arch cross-sectional lesion and macrophage area were unaffected by atorvastatin, decreased 72-80% by CI-976 and reduced 87-92% upon coadministration. We conclude that inhibition of HMG-CoA reductase and ACAT acts synergistically to lower plasma total and lipoprotein cholesterol levels and to limit the development of atherosclerotic lesions in the cholesterol-fed rabbit by presumably regulating cholesterol trafficking pathways within liver and vascular cells.
鉴于HMG-CoA还原酶抑制剂和ACAT抑制剂对高胆固醇血症和动脉粥样硬化具有有益作用，我们推测联合用药将改善降血脂反应，不仅能限制病变发展，还能改变动脉粥样硬化病变的细胞组成，从而诱导出稳定的动脉粥样硬化病变形态。阿托伐他汀（2.5mg/kg）和CI-976（5mg/kg）分别使血浆总胆固醇暴露量降低了29%和39%，联合用药时降低了60%，这主要是由于极低密度脂蛋白胆固醇的减少。单独使用阿托伐他汀或CI-976时，肝脏胆固醇酯（CE）含量有适度变化；然而，联合用药时显著降低了48%。胆固醇喂养使肝脏HMG-CoA还原酶mRNA水平降低了73%，药物治疗未能阻止这种降低；但是，单独使用阿托伐他汀以及联合用药时，低密度脂蛋白受体mRNA水平的降低有所减弱。阿托伐他汀对髂股动脉的CE含量没有影响，但CI-976使其降低了35%，联合用药时降低了53%。阿托伐他汀使胸主动脉CE含量降低了38%，CI-976使其降低了48%，联合用药时降低了80%。阿托伐他汀分别使髂股动脉病变和巨噬细胞面积减少了48%和67%，CI-976分别使其减少了68%和81%，但联合用药时仅观察到巨噬细胞面积减少了85%。阿托伐他汀对主动脉弓横截面病变和巨噬细胞面积没有影响，CI-976使其减少了72%-80%，联合用药时减少了87%-92%。我们得出结论，抑制HMG-CoA还原酶和ACAT具有协同作用，可降低血浆总胆固醇和脂蛋白胆固醇水平，并通过调节肝脏和血管细胞内的胆固醇转运途径，限制胆固醇喂养兔动脉粥样硬化病变的发展。
