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Low human and murine Mcl-1 expression leads to a pro-apoptotic plaque phenotype enriched in giant-cells.

Publication ,  Journal Article
Fontaine, MAC; Westra, MM; Bot, I; Jin, H; Franssen, AJPM; Bot, M; de Jager, SCA; Dzhagalov, I; He, Y-W; van Vlijmen, BJM; Gijbels, MJJ ...
Published in: Sci Rep
October 10, 2019

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-1fl/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.

Duke Scholars

Published In

Sci Rep

DOI

EISSN

2045-2322

Publication Date

October 10, 2019

Volume

9

Issue

1

Start / End Page

14547

Location

England

Related Subject Headings

  • Plaque, Atherosclerotic
  • Phenotype
  • Neutrophils
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Mice, Transgenic
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Macrophages
  • Lipids
 

Citation

APA
Chicago
ICMJE
MLA
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Fontaine, M. A. C., Westra, M. M., Bot, I., Jin, H., Franssen, A. J. P. M., Bot, M., … Biessen, E. A. L. (2019). Low human and murine Mcl-1 expression leads to a pro-apoptotic plaque phenotype enriched in giant-cells. Sci Rep, 9(1), 14547. https://doi.org/10.1038/s41598-019-51020-3
Fontaine, Margaux A. C., Marijke M. Westra, Ilze Bot, Han Jin, Aimée J. P. M. Franssen, Martine Bot, Saskia C. A. de Jager, et al. “Low human and murine Mcl-1 expression leads to a pro-apoptotic plaque phenotype enriched in giant-cells.Sci Rep 9, no. 1 (October 10, 2019): 14547. https://doi.org/10.1038/s41598-019-51020-3.
Fontaine MAC, Westra MM, Bot I, Jin H, Franssen AJPM, Bot M, et al. Low human and murine Mcl-1 expression leads to a pro-apoptotic plaque phenotype enriched in giant-cells. Sci Rep. 2019 Oct 10;9(1):14547.
Fontaine, Margaux A. C., et al. “Low human and murine Mcl-1 expression leads to a pro-apoptotic plaque phenotype enriched in giant-cells.Sci Rep, vol. 9, no. 1, Oct. 2019, p. 14547. Pubmed, doi:10.1038/s41598-019-51020-3.
Fontaine MAC, Westra MM, Bot I, Jin H, Franssen AJPM, Bot M, de Jager SCA, Dzhagalov I, He Y-W, van Vlijmen BJM, Gijbels MJJ, Reutelingsperger CP, van Berkel TJC, Sluimer JC, Temmerman L, Biessen EAL. Low human and murine Mcl-1 expression leads to a pro-apoptotic plaque phenotype enriched in giant-cells. Sci Rep. 2019 Oct 10;9(1):14547.

Published In

Sci Rep

DOI

EISSN

2045-2322

Publication Date

October 10, 2019

Volume

9

Issue

1

Start / End Page

14547

Location

England

Related Subject Headings

  • Plaque, Atherosclerotic
  • Phenotype
  • Neutrophils
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Mice, Transgenic
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Macrophages
  • Lipids