Abstract 8090: Identification Of Rcn2 As A Novel Regulator Of Cytokine Expression
Background- Ath29 is an atherosclerosis susceptibility locus on chromosome 9 identified in an intercross between C57BL/6 (B6) and C3H/HeJ (C3H) apolipoprotein E-deficient (apoE−/−) mice. This locus was subsequently replicated in two separate intercrosses that developed early or advanced atherosclerotic lesions. The objective of this study was to characterize Ath29 through construction and analysis of a congenic strain and identify underlying candidate genes.
Methods and Results- Congenic strain was constructed by introgressing the chromosomal segment harboring Ath29 from C3H.apoE−/− into B6.apoE−/− mice. Congenic mice developed significantly smaller early and advance atherosclerotic lesions than B6.apoE−/− mice. Microarray analysis revealed 317 genes to be differentially expressed in the aorta of congenic mice compared with B6.apoE−/− mice. Pathway analysis of these genes suggested the calcium signaling pathway to be implicated in regulating atherosclerosis susceptibility. Rcn2 is located underneath the linkage peak of Ath29 and involved in calcium signaling. Multiple SNPs between B6 and C3H mice were detected within and surrounding Rcn2 with one SNP falling within an upstream cAMP response element. Immunostaining demonstrated its expression in atherosclerotic lesions. Knockdown of Rcn2 with siRNAs resulted in significant reductions in both baseline and oxidized phospholipid-induced VCAM-1 and MCP-1 expression by endothelial cells.
Conclusions- Ath29 is confirmed to be a major atherosclerosis susceptibility locus affecting both early and advanced lesion formation in mice, and Rcn2 is identified as a novel regulator of cytokine expression.
- © 2011 by American Heart Association, Inc.