GM-CSF deficiency reduces macrophage PPAR-gamma expression and aggravates atherosclerosis in ApoE-deficient mice.

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% (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-gamma, ABCA1, and CD36 in lesions showed reduced expression (50%, 65%, and 55%, respectively), whereas SR-A doubled. In peritoneal macrophages, PPAR-gamma 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)-alpha 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-gamma and ABCA1, molecules that affect cholesterol homeostasis and inflammation.

• Authors: Michael Ditiatkovski, Ban-Hock Toh, Alex Bobik
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 26 Issue 10 Pg. 2337-44 (Oct 2006) ISSN: 1524-4636 [Electronic] United States
• PMID: 16873730 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP Binding Cassette Transporter 1
• ATP-Binding Cassette Transporters
• Apolipoproteins E
• Ccl2 protein, mouse
• Chemokine CCL2
• PPAR gamma
• Tumor Necrosis Factor-alpha
• Vascular Cell Adhesion Molecule-1
• Granulocyte-Macrophage Colony-Stimulating Factor
• Collagen
• Cholesterol

Topics

• ATP Binding Cassette Transporter 1
• ATP-Binding Cassette Transporters (antagonists & inhibitors)
• Animals
• Apolipoproteins E (deficiency)
• Atherosclerosis (etiology, metabolism, pathology)
• Chemokine CCL2 (metabolism)
• Cholesterol (metabolism)
• Collagen (antagonists & inhibitors)
• Granulocyte-Macrophage Colony-Stimulating Factor (deficiency, metabolism)
• Hyperlipidemias (complications)
• Macrophages (metabolism, pathology)
• Macrophages, Peritoneal (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Neovascularization, Pathologic (pathology)
• PPAR gamma (antagonists & inhibitors)
• Sinus of Valsalva (metabolism)
• Tumor Necrosis Factor-alpha (metabolism)
• Up-Regulation
• Vascular Cell Adhesion Molecule-1 (metabolism)