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Published on: April 3, 2017
Reduced macrophage apoptosis is associated with accelerated atherosclerosis in low-density lipoprotein receptor-null
June Liu1, Douglas P Thewke, Yan Ru Su
1Department of Biochemistry and Molecular Biology, East Tennessee State University, Johnson City, TN 37614, USA.
Objective:
The majority of apoptotic cells in atherosclerotic lesions are macrophages. However, the pathogenic role of macrophage apoptosis in the development of atherosclerosis remains unclear. Elevated expression of Bax, one of the pivotal proapoptotic proteins of the Bcl-2 family, has been found in human atherosclerotic plaques. Activation of Bax also occurs in free cholesterol-loaded and oxysterol-treated mouse macrophages. In this study, we examined the effect of Bax deficiency in bone marrow-derived leukocytes on the development of atherosclerosis in low-density lipoprotein receptor-null (LDLR-/-) mice.
Methods And Results:
Fourteen 8-week-old male LDLR-/- mice were lethally irradiated and reconstituted with either wild-type (WT) C57BL6 or Bax-null (Bax-/-) bone marrow. Three weeks later, the mice were challenged with a Western diet for 10 weeks. No differences were found in the plasma cholesterol level between the WT and Bax-/- group. However, quantitation of cross sections from proximal aorta revealed a 49.2% increase (P=0.0259) in the mean lesion area of the Bax-/- group compared with the WT group. A 53% decrease in apoptotic macrophages in the Bax-/- group was found by TUNEL staining (P<0.05).
Conclusions:
The reduction of apoptotic activity in macrophages stimulates atherosclerosis in LDLR-/- mice, which is consistent with the hypothesis that macrophage apoptosis suppresses the development of atherosclerosis.
Insights
Macrophage apoptosis normally suppresses atherosclerosis. Bax deficiency in macrophages reduced apoptosis, significantly increasing atherosclerotic lesion size in mice, supporting this protective role.
Area of Science:
- Cardiovascular Biology
- Immunology
- Atherosclerosis Research
Background:
- Macrophages are the predominant apoptotic cells in atherosclerotic lesions.
- The role of macrophage apoptosis in atherosclerosis pathogenesis is not fully understood.
- Bax, a proapoptotic protein, is elevated in human atherosclerotic plaques and activated in macrophages.
Purpose of the Study:
- To investigate the impact of Bax deficiency in bone marrow-derived leukocytes on atherosclerosis development.
- To determine if reduced macrophage apoptosis influences atherosclerotic lesion progression in low-density lipoprotein receptor-null (LDLR-/-) mice.
Main Methods:
- Bone marrow from wild-type (WT) or Bax-null (Bax-/-) mice was used to reconstitute lethally irradiated LDLR-/- mice.
- Mice were fed a Western diet for 10 weeks to induce atherosclerosis.
- Plasma cholesterol, aortic lesion area, and macrophage apoptosis (TUNEL staining) were quantified.
Main Results:
- No significant difference in plasma cholesterol levels between WT and Bax-/- groups.
- Bax-/- mice exhibited a 49.2% increase in mean aortic lesion area compared to WT controls.
- Macrophage apoptosis was reduced by 53% in the Bax-/- group.
Conclusions:
- Reduced apoptotic activity in macrophages accelerates atherosclerosis development in LDLR-/- mice.
- These findings support the hypothesis that macrophage apoptosis plays a suppressive role in atherosclerosis progression.
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