| First Author | Fontaine MAC | Year | 2019 |
| Journal | Sci Rep | Volume | 9 |
| Issue | 1 | Pages | 14547 |
| PubMed ID | 31601924 | Mgi Jnum | J:284252 |
| Mgi Id | MGI:6389386 | Doi | 10.1038/s41598-019-51020-3 |
| Citation | Fontaine MAC, et al. (2019) Low human and murine Mcl-1 expression leads to a pro-apoptotic plaque phenotype enriched in giant-cells. Sci Rep 9(1):14547 |
| abstractText | The anti-apoptotic protein myeloid cell leukemia 1 (Mcl-1) plays an important role in survival and differentiation of leukocytes, more specifically of neutrophils. Here, we investigated the impact of myeloid Mcl-1 deletion in atherosclerosis. Western type diet fed LDL receptor-deficient mice were transplanted with either wild-type (WT) or LysMCre Mcl-1(fl/fl) (Mcl-1(-/-)) bone marrow. Mcl-1 myeloid deletion resulted in enhanced apoptosis and lipid accumulation in atherosclerotic plaques. In vitro, Mcl-1 deficient macrophages also showed increased lipid accumulation, resulting in increased sensitivity to lipid-induced cell death. However, plaque size, necrotic core and macrophage content were similar in Mcl-1(-/-) compared to WT mice, most likely due to decreased circulating and plaque-residing neutrophils. Interestingly, Mcl-1(-/-) peritoneal foam cells formed up to 45% more multinucleated giant cells (MGCs) in vitro compared to WT, which concurred with an increased MGC presence in atherosclerotic lesions of Mcl-1(-/-) mice. Moreover, analysis of human unstable atherosclerotic lesions also revealed a significant inverse correlation between MGC lesion content and Mcl-1 gene expression, coinciding with the mouse data. Taken together, these findings suggest that myeloid Mcl-1 deletion leads to a more apoptotic, lipid and MGC-enriched phenotype. These potentially pro-atherogenic effects are however counteracted by neutropenia in circulation and plaque. |
