Abstract 3966: Absence of Macrophage Mcl-1 Induces Foam Cell Formation and Atherosclerotic Plaque Apoptosis without Affecting Plaque Development in LDLr−/− Mice
Anti-apoptotic Bcl-2 family member myeloid cell leukemia 1 (Mcl-1) plays an important, in neutrophils essential, role in promoting survival and differentiation of leukocyte subsets. Mcl-1 was shown to be responsible for IL-10 dependent inhibition of macrophage apoptosis in response to oxidized LDL in vitro. In this study we have investigated the role of myeloid Mcl-1 deficiency in atherosclerotic plaque development and stability. LDLr−/− mice were lethally irradiated and transplanted with bone marrow from transgenic mice with myeloid specific Mcl-1 deficiency (Mcl-1−/−) or WT littermates. After a recovery period of 8 weeks, the mice were fed a high-fat diet for 10 weeks to induce atherosclerotic lesion development in the aortic root. Peritoneal leukocytes were analyzed for foam cell numbers and sensitivity towards Ox-LDL. The number of foam cells among the resting peritoneal leukocyte population showed a 2,5 fold (p=0.02) increase in Mcl-1−/− mice compared to WT controls. After Ox-LDL stimulation lipid accumulation by Mcl-1−/− macrophages was dramatically increased by 5 fold (p=0.01). Furthermore, peritoneal macrophages from Mcl-1−/− mice showed an increased sensitivity towards ox-LDL induced cell death compared to WT macrophages (39.3 ± 0.9 % and 24.1 ± 1.51 % respectively, p=0.0001). In atherosclerotic aortic root lesions of Mcl-1−/− mice apoptotic cell content was elevated by 77% (p=0.002) compared to WT controls. However, despite these pro-atherogenic effects, atherosclerotic lesion size did not differ between Mcl-1−/− and WT mice. As Mcl-1 is essential for neutrophil survival, neutrophil numbers in whole blood were measured and shown to be decreased by 91% (p=0.001) in Mcl-1−/− mice while neutrophil infiltration in the atherosclerotic plaque was decreased by only 50%. This apparent paradox may be attributable to the enhancing migratory capacity of residual neutrophils, as neutrophil CXCR4 expression was elevated in Mcl-1−/− mice. In conclusion, Mcl-1 influences ox-LDL induced foam cell formation and cell death in vivo, and although the apoptotic cell content is largely increased, its deficiency does not affect atherosclerotic plaque growth. Further research is necessary to elucidate the exact mechanisms of these findings.