Genomics of foam cells and nonfoamy macrophages from rabbits identifies arginase-I as a differential regulator of nitric oxide production

Objective-Conversion of macrophages to foam cells is a critical step in the initiation and progression of atherosclerosis. We sought to identify genes differentially regulated in foam cells, since these are likely to include new targets for intervention. Methods and Results-We used suppression subtraction hybridization to compare foam cells and nonfoamy macrophages isolated from subcutaneous granulomas of rabbits fed a cholesterol-rich or normal chow diet and confirmed upregulation of 3 genes, including matrix metalloproteinase-12 (mRNA 2.0-fold, P < 0.005; protein 3.9- fold, P < 0.03). Arginase-I mRNA showed the biggest decrease among 11 downregulated genes in foam cells (2.7-fold, P < 0.001) and was accompanied by significantly reduced arginase enzymatic activity (60-fold, P < 0.01). Arginase-I competes for substrate L-arginine with nitric oxide synthase and consequently nitric oxide production was significantly increased (3-fold, P < 0.02) in foam cells compared with nonfoamy macrophages despite no difference in nitric oxide synthase isoenzyme expression. We validated upregulation of matrix metalloproteinase-12 and downregulation of arginase-1 in foam cells of rabbit and human atherosclerotic plaques. Conclusions-Our study identified several differentially expressed genes in foam cells and nonfoamy macrophages derived from live rabbits. The altered pattern of gene expression in foam cells is likely to influence atherosclerosis formation and stability.