Yap Jonathan, McCurdy Sara, Alcala Martin, Irei Jason, Garo Jan, Regan Whitney, Lee Bog-Hieu, Kitamoto Shiro, Boisvert William A
Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, United States.
Department of Chemistry and Biochemistry, Facultad de Farmacia, Universidad CEU San Pablo, Madrid, Spain.
Front Physiol. 2020 Jun 23;11:714. doi: 10.3389/fphys.2020.00714. eCollection 2020.
To determine whether overexpression of the chitin degrading enzyme, chitotriosidase (CHIT1), modulates macrophage function and ameliorates atherosclerosis.
Using a mouse model that conditionally overexpresses CHIT1 in macrophages (CHIT1-Tg) crossbred with the mouse provided us with a means to investigate the effects of CHIT1 overexpression in the context of atherosclerosis. , CHIT1 overexpression by murine macrophages enhanced protein expression of IL-4, IL-8, and G-CSF by BMDM upon stimulation with a combination of lipopolysaccharide (LPS) and interferon-γ (IFN-γ). Phosphorylation of ERK1/2 and Akt was also down regulated when exposed to the same inflammatory stimuli. Hyperlipidemic, -CHIT1-Tg (CHIT1-OE) mice were fed a high-fat diet for 12 weeks in order to study CHIT1 overexpression in atherosclerosis. Although plaque size and lesion area were not affected by CHIT1 overexpression , the content of hyaluronic acid (HA) and collagen within atherosclerotic plaques of CHIT1-OE mice was significantly greater. Localization of both ECM components was markedly different between groups.
These data demonstrate that CHIT1 alters cytokine expression and signaling pathways of classically activated macrophages. , CHIT1 modifies ECM distribution and content in atherosclerotic plaques, both of which are important therapeutic targets.
确定几丁质降解酶壳三糖苷酶（CHIT1）的过表达是否会调节巨噬细胞功能并改善动脉粥样硬化。
利用一种在巨噬细胞中条件性过表达CHIT1的小鼠模型（CHIT1-Tg）与 小鼠杂交，为我们提供了一种在动脉粥样硬化背景下研究CHIT1过表达影响的方法。小鼠巨噬细胞过表达CHIT1可增强骨髓来源的巨噬细胞（BMDM）在脂多糖（LPS）和干扰素-γ（IFN-γ）联合刺激下IL-4、IL-8和G-CSF的蛋白表达。当暴露于相同的炎症刺激时，ERK1/2和Akt的磷酸化也下调。为了研究CHIT1在动脉粥样硬化中的过表达，给高脂血症的CHIT1-Tg（CHIT1-OE）小鼠喂食高脂饮食12周。尽管斑块大小和病变面积不受CHIT1过表达的影响，但CHIT1-OE小鼠动脉粥样硬化斑块内透明质酸（HA）和胶原蛋白的含量显著更高。两组之间两种细胞外基质成分的定位明显不同。
这些数据表明，CHIT1改变经典活化巨噬细胞的细胞因子表达和信号通路。此外，CHIT1改变动脉粥样硬化斑块中细胞外基质的分布和含量，这两者都是重要的治疗靶点。
