on July 27, 2006
Published online before print July 27, 2006, doi: 10.1161/01.ATV.0000238357.60338.90
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Submitted on February 9, 2006
Accepted on July 9, 2006
GM-CSF Deficiency Reduces Macrophage PPAR-
Expression and Aggravates Atherosclerosis in ApoE-Deficient Mice
Michael Ditiatkovski *;
From the Cell Biology Laboratory (M.D., A.B.), Baker Heart Research Institute and Autoimmunity Laboratory (M.D., B.-H.T.), Department of Immunology, Monash University, AMREP, Alfred Campus, Melbourne, Victoria, Australia. Present address for B.-H.T.: Centre for Inflammatory Diseases, Monash Institute of Medical Research, Monash University, Clayton, Victoria 3168, Australia.
* To whom correspondence should be addressed. E-mail: Michael.Ditiatkovski{at}baker.edu.au.
Objective--Granulocyte-macrophage colony-stimulating factor (GM-CSF) is expressed in atherosclerotic lesions but its significance for lesion development is unknown. Consequently, we investigated the significance of GM-CSF expression for development of atherosclerotic lesions in apolipoprotein E (apoE)-deficient (apoE-/-) mice.
Methods and Results--We generated apoE-/- mice deficient in GM-CSF (apoE-/-.GM-CSF-/- mice), fed them a high-fat diet, and compared lesion development with apoE-/- mice. We measured lesion size, macrophage, smooth muscle cell, and collagen accumulation at the aortic sinus, and expression of genes that regulate cholesterol transport and inflammation. No differences in serum cholesterol were found between the 2 groups. Lesion size in hyperlipidemic apoE-/-.GM-CSF-/- increased by 30% (P<0.05), macrophage accumulation doubled, and collagen content reduced by 15% (P<0.05); smooth muscle cell accumulation and vascularity were unaffected. Analysis of PPAR-
, ABCA1, and CD36 in lesions showed reduced expression (50%, 65%, and 55%, respectively), whereas SR-A doubled. In peritoneal macrophages, PPAR- and ABCA1 expression was also reduced by 50% and 70%, respectively, as was cholesterol efflux, by 50%. In lesions, pro-inflammatory MCP-1 and tumor necrosis factor (TNF)-
expression increased 2- and 3.5-fold, respectively, vascular cell adhesion molecule (VCAM)-1 expression enhanced and interleukin (IL)-1 receptor antagonist reduced by 50%.
Conclusions--GM-CSF deficiency increases atherosclerosis under hypercholesterolemic conditions, indicating antiatherogenic role for GM-CSF. We suggest this protective role is mediated by PPAR- and ABCA1, molecules that affect cholesterol homeostasis and inflammation.
Key words: apoE-/- mice • atherosclerotic lesions • GM-CSF deficiency • hyperlipidemia • inflammatory cytokines • PPAR-
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