Interactions of platelets, macrophages, and lipoproteins in hypercholesterolemia: antiatherogenic effects of HMG-CoA reductase inhibitor therapy.

To assess the effect of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors on plasma cholesterol concentrations and on platelet aggregation, lovastatin or fluvastatin, 40 mg daily, was given to hypercholesterolemic patients. After 24 weeks, plasma low-density lipoprotein (LDL) cholesterol concentrations were reduced by 37% after lovastatin therapy and 29% after fluvastatin therapy. The platelet cholesterol/phospholipid ratio was reduced by 33% and 26%, respectively. Platelet aggregation was significantly reduced by 12-15% (p < 0.01) after 4 weeks of therapy with either agent. Lovastatin or fluvastatin therapy reduced platelet aggregation through an in vivo hypocholesterolemic action on the platelet cholesterol content and also through a direct effect on platelet function, as a result of drug binding to the platelets. We also studied the effect of these HMG-CoA reductase inhibitors on LDL susceptibility to oxidation. LDL oxidation (induced by copper ions) was reduced by 31% after lovastatin therapy and by 37% after fluvastatin therapy. The inhibitory effect of HMG-CoA reductase inhibitors on LDL oxidation involved their stimulatory effect on the removal of LDL from the circulation and a direct binding effect of the drugs to the lipoprotein. Because HMG-CoA reductase inhibitors can inhibit platelet aggregation, macrophage foam cell formation, and LDL oxidation, major contributors to atherogenesis, the use of these drugs can significantly attenuate the atherosclerotic process.