Interactions of Platelets, Macrophages, and Lipoproteins in Hypercholesterolemia: Antiatherogenic Effects of HMG-CoA Reductase Inhibitor Therapy

Abstract

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.

Atorvastatin Upregulates Type III Nitric Oxide Synthase in Thrombocytes, Decreases Platelet Activation, and Protects From Cerebral Ischemia in Normocholesterolemic Mice

“…45 Moreover, several recent studies have demonstrated beneficial effects of statin therapy on platelet function and fibrinolysis in hypercholesterolemic individuals. [45][46][47][48][49][50][51] Our findings, by contrast, demonstrate that statins inhibit platelet activation independent of serum cholesterol levels by upregulation of type III NOS. Therefore, our data may have direct clinical implications: eNOS upregulation may be the mechanism of protection in patients with average cholesterol levels, as observed in large statin trials.…”

Fluvastin therapy affects TAFI concentration in kidney transplant recipients

“…On the other hand, P-selectin, though it may be derived from either platelets and/or endothelium [20], has potential as a new marker of platelet activation [21]. Platelet activity is enhanced in hypercholesterolaemia and may be a crucial factor in the pathogenesis of atherosclerotic lesion formation, and at least partially in the occurrence of cardiovascular events [22]. Activated platelets tend to aggregate and are found close to atherosclerotic plaques [23].…”

Beneficial Cardiovascular Pleiotropic Effects of Statins

“…21,22 Hydroxy metabolites of atorvastatin, but not the parent compound, inhibit oxidation of both LDL and very-low-density lipoprotein as well as high-density lipoprotein. 23 In addition, the hydroxy metabolites, representing 70% of active atorvastatin in plasma, demonstrate free radical-scavenging abilities that may contribute to inhibition of lipoprotein oxidation.…”