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.


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.
Thomas
Anita C
AC
Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Bristol, BS2 8HW, United Kingdom.
Sala-Newby
Graciela B
GB
Ismail
Yasmin
Y
Johnson
Jason L
JL
Pasterkamp
Gerard
G
Newby
Andrew C
AC
D000818:Animals; D001119:Arginase / Q000378:metabolism* / Q000494:pharmacology; D050197:Atherosclerosis / Q000235:genetics / Q000503:physiopathology*; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D004195:Disease Models, Animal; D015536:Down-Regulation; D005487:Foam Cells / Q000378:metabolism*; D005786:Gene Expression Regulation; D023281:Genomics; D008264:Macrophages / Q000378:metabolism*; D053508:Matrix Metalloproteinase 12 / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis*; D011336:Probability; D011817:Rabbits; D012680:Sensitivity and Specificity; D015854:Up-Regulation
D002791:Cholesterol, Dietary; D009569:Nitric Oxide; D053508:Matrix Metalloproteinase 12; D001119:Arginase