title: Chitinase inhibition promotes atherosclerosis in hyperlipidemic mice.
abstract: Chitinase 1 (CHIT1) is secreted by activated macrophages. Chitinase activity is raised in atherosclerotic patient sera and is present in atherosclerotic plaque. However, the role of CHIT1 in atherosclerosis is unknown. Preliminary studies of atherosclerosis in cynomolgous monkeys revealed CHIT1 to be closely correlated with areas of macrophage infiltration. Thus, we investigated the effects of a chitinase inhibitor, allosamidin, on macrophage function in vitro and on atherosclerotic development in vivo. In RAW264.7 cells, allosamidin elevated monocyte chemoattractant protein 1 and tumor necrosis factor alpha expression, and increased activator protein 1 and nuclear factor-κB transcriptional activity. Although inducible nitric oxide synthase, IL-6, and IL-1β expression were increased, Arg1 expression was decreased by chitinase inhibition, suggesting that suppression of CHIT1 activity polarizes macrophages into a M1 phenotype. Allosamidin decreased scavenger receptor AI, CD36, ABCA1, and ABCG1 expression which led to suppression of cholesterol uptake and apolipoprotein AI-mediated cholesterol efflux in macrophages. These effects were confirmed with CHIT1 siRNA transfection and CHIT1 plasmid transfection experiments in primary macrophages. Apolipoprotein E-deficient hyperlipidemic mice treated for 6 weeks with constant administration of allosamidin and fed an atherogenic diet showed aggravated atherosclerotic lesion formation. These data suggest that CHIT1 exerts protective effects against atherosclerosis by suppressing inflammatory responses and polarizing macrophages toward an M2 phenotype, and promoting lipid uptake and cholesterol efflux in macrophages.
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. shiro_kt@cardiol.med.kyushu-u.ac.jp
authors.forename: Shiro
authors.initials: S
authors.lastname: Kitamoto
authors.forename: Kensuke
authors.initials: K
authors.lastname: Egashira
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Ichiki
authors.forename: Xinbing
authors.initials: X
authors.lastname: Han
authors.forename: Sara
authors.initials: S
authors.lastname: McCurdy
authors.forename: Shohei
authors.initials: S
authors.lastname: Sakuda
authors.forename: Kenji
authors.initials: K
authors.lastname: Sunagawa
authors.forename: William A
authors.initials: WA
authors.lastname: Boisvert
mesh_terms: D000117:Acetylglucosamine / Q000009:adverse effects / Q000031:analogs & derivatives*; D000818:Animals; D050197:Atherosclerosis / Q000139:chemically induced / Q000201:enzymology* / Q000378:metabolism / Q000517:prevention & control; D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D002688:Chitinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000009:adverse effects*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014312:Trisaccharides / Q000009:adverse effects*
chemical_list: D015415:Biomarkers; D016207:Cytokines; D004791:Enzyme Inhibitors; D014312:Trisaccharides; C054851:allosamidin; D002688:Chitinases; D000117:Acetylglucosamine