Nitric oxide synthase II (NOS II) gene expression correlates with atherosclerotic intimal thickening. Preventive effects of HMG-CoA reductase inhibitors

HMG-CoA reductase inhibitors have been shown to be effective in primary and secondary prevention of coronary heart disease. Their mechanism of action is attributed to their cholesterol lowering activity but recent results see m to indicate additional effects related to the modulation of other process es that regulate the presentation of vascular diseases. Our objective has b een to study the effects of atorvastatin and simvastatin, two HMG-CoA reduc tase inhibitors, on lesion composition and expression of genes involved in lesion development in a diet-induced atherosclerotic rabbit model. Both HMG -CoA reductase inhibitors were administered at identical doses of 2.5 mg/kg per day with the hyperlipemic diet for 10 weeks. Both statins significantl y prevented the diet-induced increase in cholesterol levels. Relative lesio n composition in fibrinogen, macrophages and smooth muscle cells was unalte red by the treatment although lesion size was reduced; therefore, both HMG- CoA reductase inhibitors reduced total amounts of fibrinogen, macrophages a nd smooth muscle cells (simvastatin, P < 0.05). NOS II gene expression was positively and significantly correlated with lesion size and inversely corr elated with HDL plasma levels. NOS II expression was markedly downregulated in simvastatin treated animals while MCP-1 was unaltered. Therefore, HMC-C oA reductase inhibition seems to interfere with atherosclerotic lesion deve lopment by reducing intimal thickening development and the expression of th e cytotoxic NOS II. (C) 1999 Elsevier Science Ireland Ltd. All rights reser ved.