Simvastatin inhibits expression of tissue factor in advanced atherosclerotic lesions of apolipoprotein E deficient mice independently of lipid lowering: potential role of simvastatin-mediated inhibition of Egr-1 expression and activation

Abstract

Recent studies suggest that the beneficial effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins) in reducing cardiovascular events may in part, be independent of their capacity to lower plasma lipids. To test this hypothesis, simvastatin (50 mg/kg/d) was administered to 30-week-old apolipoprotein E deficient mice (apo E-/-) for 12, 18 and 24 weeks. In contrast to other experimental models and humans, simvastatin treatment increases plasma cholesterol levels in apo E-/- mice. Quantitative real-time polymerase chain reaction was used to quantify expression of tissue factor (TF) and monocyte chemoattractant protein-1 (MCP-1) in the aorta of each mouse. Expression of TF was reduced to 34, 24, and 13% of control levels at 12, 18 and 24 weeks, respectively, of simvastatin administration. Advanced lesions in the innominate arteries of the simvastatin treated mice had reduced levels of TF, fewer macrophages and reduced expression of early growth response-1 (Egr-1). In vitro studies in mouse macrophages demonstrated decreased lipopolysaccharide induced binding of nuclear proteins to the Egr-1 consensus DNA sequence following pretreatment with simvastatin. RNA levels for MCP-1 were reduced to 30% of control values following 24 weeks of simvastatin treatment. In conclusion, these data suggest that chronic administration of simvastatin to older apo E-/- mice can inhibit the expression of pro-thrombotic/pro-inflammatory genes within established atherosclerotic lesions via mechanisms that are independent of reductions in plasma lipids.