Abstract 15387: Mice Double-Deficient for Apolipoprotein E and Biglycan Show Enhanced Atherosclerosis on Normal Chow
Objective: The small leucine-rich proteoglycan biglycan is postulated to play on the one hand a key role in collagen matrix assembly and on the other hand in lipid retention due to its LDL-binding properties.
Methods: To analyse the functional role of biglycan in atherosclerosis male mice double deficient of apolipoprotein E and biglycan (ApoE−/−/bgn−/0) were bred and analysed concerning atherogenesis and the progression of atherosclerosis compared to ApoE deficient littermates (ApoE−/−/bgn+/0) at 15 and 30 weeks on normal chow.
Results: ApoE−/−/bgn−/0 mice showed dramatically increased plaque burden as determined by oil-red O en face staining of the aorta that was associated with dilatation of the aortic arch in comparison to age matched littermates. While there were no differences found in lipid retention of the aortic root plaques, the collagen content was slightly increased while collagen fibril density was decreased in ApoE−/−bgn−/0 double deficient mice as evidenced by sirius red staining. Furthermore, atherosclerotic lesions of ApoE−/−/bgn−/0 mice were characterized by decreased accumulation of hyaluronic acid. In order to study the mechanisms responsible for increased atherosclerosis the vascular and systemic inflammatory response was characterized. ApoE−/−bgn−/0 mice show dramatically increased macrophage retention in aortic root lesions at 15 weeks evidenced by MAC2 and F4/80 expression. Plasma concentrations of pro-inflammatory cytokines interleukin 2, 3 and 6 were increased as well as the macrophage attracting chemokines MCP1 and MIP1-alpha in ApoE−/−/bgn−/0 mice at 15 weeks, while anti-inflammatory interleukin 4 was downregulated. Furthermore isolated peritoneal macrophages showed dramatic increased secretion of TNF-alpha, MCP-1, Rantes and interleukin 6 after 4 h treatment with either LPS or Peptidoglycan.
Conclusion: ApoE−/−/bgn−/0 mice developed increased atherosclerosis compared to their ApoE−/− littermates on normal chow due to an increased inflammation. These results suggest that vascular expression of biglycan may inhibit vascular inflammation during initiation and progression of atherosclerosis.
- © 2010 by American Heart Association, Inc.