Identification of macrophage arginase I as a new candidate gene of atherosclerosis resistance.
OBJECTIVE
Our laboratory has previously created 2 strains of rabbits with genetically determined high-atherosclerotic response (HAR) and low-atherosclerotic response (LAR). The aim of the present study was to identify new genes of atherosclerosis susceptibility in macrophages from the 2 strains.


RESULTS
Suppression subtractive hybridization was used to screen for genes with higher expression in macrophages from LAR rabbits. We identified a cDNA fragment with high homology to human arginase I (AI; 91%) and subsequently cloned the full-length cDNA of the rabbit homologue. Quantitative RT-PCR revealed a significantly higher macrophage AI mRNA expression in LAR rabbits than in HAR rabbits (77428+/-10941 versus 34344+/-4538; P=0.002; copies/10(6) copies beta-actin), which also correlated with a significantly higher arginase enzyme activity. Northern blot analysis led to the identification of a size polymorphism of AI mRNA. This was because of a 413 bp C-repeat insertion in the 3' untranslated region. The shorter transcript variant was predominantly expressed in LAR rabbits and associated with significantly higher AI mRNA expression levels. Transfection experiments indicated decreased mRNA stability of the long AI variant.


CONCLUSIONS
High expression of arginase I in macrophages may contribute to atherosclerosis resistance of LAR rabbits, possibly by conferring antiinflammatory effects in the vessel wall.
Teupser
Daniel
D
Institute of Laboratory Medicine, Clinical Chemistry, and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany.
Burkhardt
Ralph
R
Wilfert
Wolfgang
W
Haffner
Ivonne
I
Nebendahl
Klaus
K
Thiery
Joachim
J
D000818:Animals; D001119:Arginase / Q000235:genetics* / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics* / Q000276:immunology*; D018076:DNA, Complementary / Q000235:genetics; D004198:Disease Susceptibility; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000201:enzymology* / Q000276:immunology; D011401:Promoter Regions, Genetic / Q000235:genetics; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics; D011817:Rabbits
D018076:DNA, Complementary; D012333:RNA, Messenger; D001119:Arginase