GM-CSF Deficiency Reduces Macrophage PPAR-γ Expression and Aggravates Atherosclerosis in ApoE-Deficient Mice

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Abstract
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-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% (PPConclusions— GM-CSF deficiency increases atherosclerosis under hypercholesterolemic conditions, indicating antiatherogenic role for GM-CSF. We suggest this protective role is mediated by PPAR-γ and ABCA1, molecules that affect cholesterol homeostasis and inflammation. We studied effect of GM-CSF deletion on atherosclerosis in apoE−/− mice. We observed increases in lesion size, macrophage accumulation, MCP-1, TNF-α, and VCAM-1; decreases in collagen content, PPAR-γ, ABCA1, and cholesterol efflux from macrophages. GM-CSF promotes smaller stable atherosclerotic lesions by mechanisms dependant on PPAR-γ and ABCA1.