Abstract 14531: Chitinase Inhibitor, Allosamidin, Accelerates Atherosclerotic Lesions in Hyperlipidemic Mice by Influencing M1/M2 Polarization and Cholesterol Metabolism in Macrophages
Objective: Chitotriosidase (Chitinase 1, CHIT1) is a glycosyl hydrolase with chitinase activity that cleaves chitin, a biopolymer ubiquitously found in insects, fungi, crustaceans, and parasites. Despite the absence of chitin in mammals, CHIT1 is abundantly secreted by activated macrophages in various human diseases. In addition, elevated chitinase activity has been reported in patients with atherosclerosis. We also observed a tight correlation between CHIT1 mRNA expression and macrophage infiltration in atherosclerotic aortae of cynomolgus monkeys. Despite this, little is known about the role of CHIT1 in the pathogenesis of atherosclerosis. In this study, we investigated the effects of chitinase inhibitor, allosamidin, in macrophage function and atherosclerosis in hyperlipidemic mice.
Methods and Results: In RAW264.7 cells, allosamidin treatment (10μ M) elevated mRNA expression of MCP-1, TNFα, iNOS, IL-6 and IL-1β; decreased mRNA expression of Arg-1; and increased AP1 and NF-κB transcriptional activity, indicating that chitinase inhibition polarizes macrophages into the M1 phenotype and promotes inflammation. Allosamidin decreased mRNA expression of SR-AI, CD36, ABCA1, and ABCG1 presumably by decreasing PPARγ and LXRα expression, and thus led to suppression of cholesterol uptake and apoAI-mediated cholesterol efflux in macrophages. For atherosclerosis study ApoE-deficient (C57BL/6.KOR/Stm Slc -Apoeshl) mice were administered allosamidin (1mg/kg/day) via subcutaneous osmotic minipump infusion while being fed a Western diet (0.15% cholesterol) for 6 weeks. Allosamidin suppressed serum chitinase activity by about 40% without influencing body weight, blood pressure or lipid profile. Chitinase inhibition increased Oil red O-stained lipid area (0.50 ± 0.28 mm2 vs. 0.77±0.24 mm2, p<0.05) and Mac3-positive macrophage infiltration area (0.061 ± 0.043 mm2 vs. 0.152 ± 0.076 mm2, p<0.05) in the aortic sinus. Atherosclerotic lesion area in the aortic arch was also aggravated by allosamidin treatment (4.9% ± 2.2 % vs. 7.9 ± 2.7%, p<0.05).
Conclusion: Chitinases play a protective role in the pathogenesis of atherosclerosis by polarizing macrophages into the M2 phenotype, suppressing inflammation, and promoting lipid uptake and efflux.
- © 2012 by American Heart Association, Inc.