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Published on: February 20, 2019
CETP Expression in Bone-Marrow-Derived Cells Reduces the Inflammatory Features of Atherosclerosis in
Thiago Rentz1, Gabriel G Dorighello1, Renata R Dos Santos2
1Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, Campinas 13083-862, SP, Brazil.
Insights
Cholesteryl ester transfer protein (CETP) expression in macrophages reduced atherosclerosis inflammation, not lesion size. This suggests CETP
Area of Science:
- Biochemistry
- Immunology
- Cardiovascular Research
Background:
- Cholesteryl ester transfer protein (CETP) activity lowers HDL-cholesterol, linked to atherosclerosis risk.
- CETP expression in macrophages may offer protective effects against inflammation and cholesterol buildup.
Purpose of the Study:
- To investigate the impact of CETP expression in bone marrow-derived cells on atherosclerosis development.
- To determine if macrophage CETP influences atherosclerotic lesion characteristics and inflammation.
Main Methods:
- Bone marrow transplantation from CETP-expressing or non-expressing mice into LDL-receptor-deficient mice.
- Analysis of atherosclerotic lesions, immune cell infiltration (macrophages, neutrophils), and inflammatory markers (TNF-α, iNOS, nitrotyrosine) in aorta.
Main Results:
- CETP expression did not alter lipid-stained lesion areas.
- CETP reduced macrophage and neutrophil content, and TNF-α in young male mice.
- CETP decreased neutrophil accumulation, TNF-α, iNOS, and nitrotyrosine in aged female mice.
Conclusions:
- Macrophage CETP expression attenuates inflammatory features of atherosclerosis.
- These findings may explain the inefficacy of CETP inhibitors in human clinical trials for atherosclerotic events.
Abstract:
CETP activity reduces plasma HDL-cholesterol concentrations, a correlate of an increased risk of atherosclerotic events. However, our recent findings suggest that CETP expression in macrophages promotes an intracellular antioxidant state, reduces free cholesterol accumulation and phagocytosis, and attenuates pro-inflammatory gene expression. To determine whether CETP expression in macrophages affects atherosclerosis development, we transplanted bone marrow from transgenic mice expressing simian CETP or non-expressing littermates into hypercholesterolemic LDL-receptor-deficient mice. The CETP expression did not change the lipid-stained lesion areas but decreased the macrophage content (CD68), neutrophil accumulation (LY6G), and TNF-α aorta content of young male transplanted mice and decreased LY6G, TNF-α, iNOS, and nitrotyrosine (3-NT) in aged female transplanted mice. These findings suggest that CETP expression in bone-marrow-derived cells reduces the inflammatory features of atherosclerosis. These novel mechanistic observations may help to explain the failure of CETP inhibitors in reducing atherosclerotic events in humans.
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