Atherosclerotic lesion progression is attenuated by reconstitution with bone marrow from macrophage-specific cholesteryl ester hydrolase transgenic mice
| Autor: | Bin Zhao, Shobha Ghosh, Jinghua Bie |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Male
Genetically modified mouse Physiology Transgene Bone Marrow Cells Mice Transgenic Biology Cholesterol Dietary Mice chemistry.chemical_compound Physiology (medical) Hydrolase Sterol esterase medicine Animals Macrophage Bone Marrow Transplantation Mice Knockout Research Macrophages Sterol Esterase Atherosclerosis Dietary Fats Molecular biology Disease Models Animal Phenotype medicine.anatomical_structure Receptors LDL Biochemistry chemistry Disease Progression Cholesteryl ester Female Bone marrow Intracellular |
| Zdroj: | American Journal of Physiology-Regulatory, Integrative and Comparative Physiology. 301:R967-R974 |
| ISSN: | 1522-1490 0363-6119 |
| DOI: | 10.1152/ajpregu.00277.2011 |
| Popis: | Accumulation of cholesteryl ester (CE)-enriched macrophage foam cells is central to the development of atherosclerotic lesions. Intracellular CE hydrolysis is the rate-limiting step in the removal of free cholesterol from macrophage foam cells. Enhancing this process by transgenic overexpression of CE hydrolase (CEH) resulted in a significant decrease in diet-induced atherosclerosis in LDL receptor-deficient (LDLR−/−) mice. However, for development of this step as an antiatherosclerotic target it is imperative to demonstrate that increase in CE hydrolysis after initiation of lesion formation will also attenuate further lesion progression. The objective of the present study was to directly address this issue using an animal model. LDLR−/− mice were fed a high-fat high-cholesterol diet (Western Diet) for 8 wk to initiate lesion formation and were then divided into three groups. Group 1 mice were killed to determine baseline lesion development. Mice in groups 2 and 3 were irradiated and transplanted with either LDLR−/− or LDLR−/−CEH transgenic bone marrow and maintained on Western Diet. Atherosclerotic lesion progression was assessed after 12 wk. While a more than fourfold increase in total lesions (compared to group 1) was seen in group 2 receiving LDLR−/− marrow, a significantly lower increase (lo). These data demonstrate for the first time that enhancing macrophage CE hydrolysis even after lesion initiation can still attenuate further lesion progression and also switches the phenotype of lesion-associated macrophages to anti-inflammatory M2 phenotype establishing intracellular CE hydrolysis as an anti-atherosclerotic as well as anti-inflammatory target. |
| Databáze: | OpenAIRE |
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