Abstract 15307: Mras-Knockout Leads to Obesity and a Lack of B-Cell Function
Background: In our recent genome-wide association study (GWAS) the MRas gene on human chromosome 3q22 displayed genome-wide significant association with coronary disease (CAD) (p=7.44x10-13). M-Ras is a member of the Ras superfamily of small GTPases, which function as molecular switches in diverse cellular functions and thereby regulate a variety of biological processes. M-Ras has been implicated in the regulation of TNFα-stimulated LFA-1 activation and integrin-mediated leukocyte adhesion downstream of various inflammatory cytokines. Aim: To further study the mechanism related to the association between MRas and CAD in a knockout mouse model.
Methods: We crossbred the MRas-KO mice onto the ApoE-KO background and fed these mice with a special high fat diet. In parallel, we performed adhesion and migration assays with macrophages, monocytes, B- and T-cells to study the influence of MRas on adhesion and migration as a potential pathomechanism of atherosclerosis.
Results: Unexpectedly, MRas-KO mice, on the single KO, but also in the MRas/ApoE-double-KO, background, developed a severe obesity phenotype Significant differences in body weight were detected for MRas-KO and MRas/ApoE double-KO - as compared to respective littermates - after 4 weeks of feeding. After 16 weeks of high fat diet an average of weight difference of 20g between groups was observed (each group 15 mice, p<0.0065). Additionally, we saw a 15% reduction of CD19+ B-cells in lymphnodes in MRas-KO mice, but not in bone marrow, spleen and blood. Furthermore, we observed a 20% reduction of leukocyte adhesion in in vitro assays with an endothelial celline (p<0.05). Again, especially B-cell adhesion is marked down in MRas-KO mice in comparison to WT mice. In vitro migration assays show also a reduced migration of B-cells towards the chemokine CxCl12 (p<0.01). The MRas/ApoE-KO mouse showed no difference in plaque formation at the aortic root in comparison to the ApoE-KO mouse after 10 weeks of high fat diet (n=19 vs n=10).
Conclusion: Our data suggests that MRas-KO has no effect on plaque formation at the aortic root; however MRas-KO leads to obesity and to a reduction of B-cell adhesion and migration.
- © 2012 by American Heart Association, Inc.