Increased atherosclerotic lesions in LDL receptor deficient mice with hematopoietic nuclear receptor Rev-erbα knock- down.

Abstract

BACKGROUND:

Nuclear receptor Rev-erbα plays important roles in circadian clock timing, lipid metabolism, adipogenesis, and vascular inflammation. However, the role of Rev-erbα in atherosclerotic lesion development has not been assessed in vivo.

METHODS AND RESULTS:

The nuclear receptor Rev-erbα was knocked down in mouse haematopoietic cells by means of shRNA-lentiviral transduction, followed by bone marrow transplantation into LDL receptor knockout mice. The Rev-erbα protein in peripheral macrophage was reduced by 70% as compared to control mice injected with nontargeting shRNA lentivirus-transduced bone marrow. A significant increase in atherosclerotic lesions was observed around the aorta valves as well as upon en face aorta analysis of Rev-erbα knock-down bone marrow recipients (P<0.01) as compared to the control mice, while plasma cholesterol, phospholipid, and triacylglycerol levels were not affected. Overexpression of Rev-erbα in bone marrow mononuclear cells decreased inflammatory M1 while increasing M2 macrophage markers, while Rev-erbα knock down increased the macrophage inflammatory phenotype in vitro and in vivo. Furthermore, treatment of differentiating macrophages with the Rev-erbα ligand heme promoted expression of antiinflammatory M2 markers.

CONCLUSIONS:

These observations identify hematopoietic cell Rev-erbα as a new modulator of atherogenesis in mice.

• Authors: Hongling Ma, Wenbin Zhong, Yingliang Jiang, Coralie Fontaine, Shiqian Li, Jiangnan Fu, Vesa M Olkkonen, Bart Staels, Daoguang Yan
• Journal: Journal of the American Heart Association (J Am Heart Assoc) Vol. 2 Issue 4 Pg. e000235 (Aug 20 2013) ISSN: 2047-9980 [Electronic] England
• PMID: 23963755 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Inflammation Mediators
• Lipids
• Nr1d1 protein, mouse
• Nuclear Receptor Subfamily 1, Group D, Member 1
• Receptors, LDL

Topics

• Animals
• Aorta (immunology, metabolism, pathology)
• Aortic Diseases (genetics, immunology, metabolism, pathology)
• Atherosclerosis (genetics, immunology, metabolism, pathology)
• Bone Marrow Transplantation
• Cells, Cultured
• Disease Models, Animal
• Gene Knockdown Techniques
• Genetic Vectors
• Genotype
• Inflammation Mediators (metabolism)
• Lentivirus (genetics)
• Lipids (blood)
• Macrophage Activation
• Macrophages (immunology, metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Nuclear Receptor Subfamily 1, Group D, Member 1 (deficiency, genetics)
• Phenotype
• RNA Interference
• Receptors, LDL (deficiency, genetics)
• Transduction, Genetic