TY - JOUR
T1 - Chitinase inhibition promotes atherosclerosis in hyperlipidemic mice
AU - Kitamoto, Shiro
AU - Egashira, Kensuke
AU - Ichiki, Toshihiro
AU - Han, Xinbing
AU - McCurdy, Sara
AU - Sakuda, Shohei
AU - Sunagawa, Kenji
AU - Boisvert, William A.
N1 - Funding Information:
Supported by a Grant-in-Aid for Young Scientists (17102) from the Ministry of Education, Culture, Sports, Science and Technology of Japan , and funds from the Takeda Science Foundation , Osaka, Japan (S.K.), by Grants-in-Aid for Scientific Research (14657172 and 14207036) from the Ministry of Education, Culture, Sports, Science, and Technology, Tokyo, Japan (K.E.), Health Science Research Grants (Comprehensive Research on Aging and Health, and on Translational Research) from the Ministry of Health Labor and Welfare, Tokyo, Japan (K.E.), and the Program for Promotion of Fundamental Studies in Health Sciences of the Organization for Pharmaceutical Safety and Research, Tokyo, Japan (K.E.), by grants from the NIH ( R01HL075677 and R01HL081863 ), and by a grant from the Hawaii Community Foundation ( 10ADVC-47037 ) (W.A.B.).
PY - 2013/7
Y1 - 2013/7
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ajpath.2013.04.003
DO - 10.1016/j.ajpath.2013.04.003
M3 - Article
C2 - 23685110
AN - SCOPUS:84879397603
VL - 183
SP - 313
EP - 325
JO - American Journal of Pathology
JF - American Journal of Pathology
SN - 0002-9440
IS - 1
ER -