Inhibition of 3-Hydroxy-3-Methylglutaryl Coenzyme A (HMG CoA) Reductase Blunts Factor VIIa/Tissue Factor and Prothrombinase Activities via Effects on Membrane Phosphatidylserine

Abstract

Objective-3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins) exhibit antithrombotic properties that are independent of reductions in circulating LDL cholesterol. We hypothesized that these antithrombotic properties are mediated by membrane alterations secondary to disrupted lipid metabolism. Methods and Results-EA.hy926 cells were incubated in the presence of 1 mol/L atorvastatin supplemented with fetal bovine serum or lipid-depleted serum mixtures. Lipid restriction alone had no effect on cell lipid composition but when atorvastatin was included, phosphatidylserine, sphingomyelin, and cholesterol were reduced by 50% while ceramide content decreased by 70%. These changes in lipid composition did not alter the association of decay accelerating factor or tissue factor with lipid rafts. Atorvastatin in combination with lipid restriction reduced factor VIIa/tissue factor activity by as much as 75% but did not alter tissue factor expression. Prothrombinase activity was reduced to an extent similar to factor VIIa/tissue factor. Mevalonic acid but not LDL reversed the observed changes in lipid content and prothrombinase activity induced by atorvastatin. These findings were confirmed in primary cells. Conclusions-Inhibition

The role of red blood cells in the progression and instability of atherosclerotic plaque

“…It has been reported that atorvastatin can change the profile of cellular phospholipids by reducing SM and ceramide-a precursor of SM-levels [58]. In light of these considerations, it is plausible that statins have a specific impact on erythrocyte membrane homeostasis and composition.…”

Statin Use is Associated with a Significant Reduction in Cholesterol Content of Erythrocyte Membranes. A Novel Pleiotropic Effect?

“…Statins are capable of lowering plasma cholesterol levels however; their beneficial effect on cardiovascular risk is dependent on mechanisms that are not easily linked to cholesterol reduction alone [26][27][28]. Reduction of endothelial dysfunction, inhibition of inflammatory responses, stabilization of atherosclerotic plaques, inhibition of vascular smooth muscle cell proliferation, improvements in endothelial nitric oxide production and a poorly understood anticoagulant effect are examples of these "pleiotropic" effects [26][27][28].…”

“…Reduction of endothelial dysfunction, inhibition of inflammatory responses, stabilization of atherosclerotic plaques, inhibition of vascular smooth muscle cell proliferation, improvements in endothelial nitric oxide production and a poorly understood anticoagulant effect are examples of these "pleiotropic" effects [26][27][28]. The cholesterol reduction of erythrocyte membranes may emerge as a novel pleiotropic effect of statins, since high CEM may be associated with clinical instability in patients with CAD [5,6,8,29].…”

“…Conversely, depletion of SM in fibroblasts resulted in a loss of cholesterol from that membrane [55]. Finally, it has been reported that atorvastatin can change the profile of cellular phospholipids by reducing SM and ceramide -a precursor of SM -levels [28]. In light of these considerations, it is plausible that statins have a specific impact on erythrocyte membrane homeostasis and composition.…”

Blood and Coagulation Support in Trauma Care

“…The nanomole of tissue factor present in every square meter of fibroblasts or smooth-muscle cells means that all of the factor VII could be removed from the circulation by 3 to 30 square meters of endothelial disruption. 23,24 Simultaneous exposure of normally subendothelial type-3 collagen binds vWF and platelets. The 250 × 10 9 platelets in a liter of blood can cover 1 square meter if lined up side by side as 2 × 2 × 2 µm cubes.…”