Abstract 14859: Mras Knockout Leads To Obesity And Affects In Atherosclerosis
Background: In our recent genome-wide association study the MRas gene on human chromosome 3q22 displayed significant association with coronary disease (p=7,44x10-13). M-Ras is a member of the Ras superfamily of small GTPases, which act as molecular switches in diverse cellular functions and thereby regulate a variety of biological processes. For example, 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 study whether MRas affects the manifestation of atherosclerosis in a knockout (KO) 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 enzyme-linked immunosorbent assays with macrophages, monocytes, B- and T-cells to study the influence of MRas on adhesion and migration as a potential pathomechanisms of atherosclerosis.
Results: Unexpectedly, the MRas-KO mice developed an obesity-like phenotype, after 16 weeks of high fat diet body weight was 53g in comparison to ApoE-KO mice (32g) and MRas-ko mice with normal diet (22g) (each group 15 mice, p<0.05). Additionally, preliminary data demonstrate a reduction of atherosclerosis in MRas/ApoE-KO mouse after high-fat diet. Furthermore, we observed a 20% reduction of leukocyte adhesion, especially B-cell adhesion in MRas-KO mice in comparison with WT mice (p<0.01).
Conclusion: Our data suggest that MRas-KO facilitates the development of obesity and a reduction of atherosclerosis in MRas/ApoE-double-KO. A potential mechanism may be the reduction of leukocyte adhesion, especially of B-cells. Thus, a reduced recruitment of B-cells might be responsible for the reduction of the atherosclerosis observed in the MRas/ApoE-double-KO mice.
- © 2011 by American Heart Association, Inc.