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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:365.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Identification of Macrophage Arginase I as a New Candidate Gene of Atherosclerosis Resistance

Daniel Teupser; Ralph Burkhardt; Wolfgang Wilfert; Ivonne Haffner; Klaus Nebendahl; Joachim Thiery

From the Institute of Laboratory Medicine, Clinical Chemistry, and Molecular Diagnostics (D.T., R.B., W.W., I.H., J.T.), University Hospital Leipzig, Leipzig; and the Department of Experimental Animal Research (K.N.), University Hospital Goettingen, Germany.

Correspondence to Joachim Thiery, Institute of Laboratory Medicine, Clinical Chemistry, and Molecular Diagnostics, University Hospital Leipzig, Liebigstr. 27, 04103 Leipzig, Germany. E-mail thiery{at}medizin.uni-leipzig.de

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.

Methods and 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/10⁶ copies ß-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.

Arginase I was identified as a new candidate gene of atherosclerosis resistance using suppression subtractive hybridization in macrophages of rabbits with low and high atherosclerotic response. High expression of arginase I in macrophages may contribute to atherosclerosis resistance, possibly by conferring antiinflammatory effects in the vessel wall.

Key Words: macrophages • gene expression • arginase I • animal models • atherosclerosis

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