Abstract | OBJECTIVE: METHODS AND RESULTS: We transplanted wild-type (WT), Mal1(-/-), or aP2(-/-) bone marrow into low-density lipoprotein receptor-null (LDLR(-/-)) mice and fed them a Western diet for 8 weeks. Mal1(-/-)→LDLR(-/-) mice had significantly reduced (36%) atherosclerosis in the proximal aorta compared with control WT→LDLR(-/-) mice. Interestingly, peritoneal macrophages isolated from Mal1-deficient mice displayed increased peroxisome proliferator-activated receptor-γ (PPARγ) activity and upregulation of a PPARγ-related cholesterol trafficking gene, CD36. Mal1(-/-) macrophages showed suppression of inflammatory genes, such as COX2 and interleukin 6. Mal1(-/-)→LDLR(-/-) mice had significantly decreased macrophage numbers in the aortic atherosclerotic lesions compared with WT→LDLR(-/-) mice, suggesting that monocyte recruitment may be impaired. Indeed, blood monocytes isolated from Mal1(-/-)→LDLR(-/-) mice on a high-fat diet had decreased CC chemokine receptor 2 gene and protein expression levels compared with WT monocytes. CONCLUSION: Taken together, our results demonstrate that Mal1 plays a proatherogenic role by suppressing PPARγ activity, which increases expression of CC chemokine receptor 2 by monocytes, promoting their recruitment to atherosclerotic lesions.
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Authors | Vladimir R Babaev, Robert P Runner, Daping Fan, Lei Ding, Youmin Zhang, Huan Tao, Ebru Erbay, Cem Z Görgün, Sergio Fazio, Gökhan S Hotamisligil, MacRae F Linton |
Journal | Arteriosclerosis, thrombosis, and vascular biology
(Arterioscler Thromb Vasc Biol)
Vol. 31
Issue 6
Pg. 1283-90
(Jun 2011)
ISSN: 1524-4636 [Electronic] United States |
PMID | 21474828
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- CD36 Antigens
- Ccr2 protein, mouse
- Fabp4 protein, mouse
- Fabp5 protein, mouse
- Fatty Acid-Binding Proteins
- Lipids
- Neoplasm Proteins
- PPAR gamma
- Receptors, CCR2
- Receptors, LDL
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Topics |
- Animals
- Atherosclerosis
(prevention & control)
- CD36 Antigens
(physiology)
- Fatty Acid-Binding Proteins
(physiology)
- Female
- Gene Expression Regulation
- Lipids
(blood)
- Macrophages
(physiology)
- Mice
- Neoplasm Proteins
(physiology)
- PPAR gamma
(physiology)
- Receptors, CCR2
(genetics)
- Receptors, LDL
(physiology)
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