Oncostatin M receptor β deficiency attenuates atherogenesis by inhibiting JAK2/STAT3 signaling in macrophages.
Oncostatin M receptor β deficiency attenuates atherogenesis by inhibiting JAK2/STAT3 signaling in macrophages.
复制标题
制瘤素 M 受体 β 缺陷通过抑制巨噬细胞中的 JAK2/STAT3 信号传导来减轻动脉粥样硬化形成
DOI：
10.1194/jlr.m074112
复制
发表时间：
2017-05
影响因子：
6.5
通讯作者：
Li H
中科院分区：
文献类型：
--
作者：
Zhang X;Li J;Qin JJ;Cheng WL;Zhu X;Gong FH;She Z;Huang Z;Xia H;Li H
抑瘤素M（Oncostatin M，OSM）是一种分泌型细胞因子，主要通过与OSM受体β（OSMR-β）结合参与慢性炎症和心血管疾病。最近的研究表明，OSM的存在有助于动脉粥样硬化斑块的不稳定。为了研究OSMR-β缺乏是否影响动脉粥样硬化，产生并使用雄性OSMR-β−/−ApoE−/−小鼠。我们观察到OSMR-β在人和小鼠动脉粥样硬化病变中表达显著上调，主要位于巨噬细胞中。我们发现，相对于ApoE缺乏的同窝仔，OSMR-β缺乏显著改善了主动脉和主动脉根部的动脉粥样硬化负荷，并通过增加胶原和平滑肌细胞含量增强了动脉粥样硬化斑块的稳定性，同时减少了巨噬细胞浸润和脂质蓄积。此外，骨髓移植OSMR-β−/−造血细胞到动脉粥样硬化倾向小鼠表现出一致的表型。此外，我们观察到JAK 2和信号转导和转录激活因子（STAT）3在体内和体外Ox-LDL刺激下的水平相对降低。我们的研究结果表明，巨噬细胞中的OSMR-β缺陷改善了高脂饮食诱导的动脉粥样硬化形成和斑块易损性。从机制上讲，OSMR-β缺乏对动脉粥样硬化的保护作用可能部分归因于抑制巨噬细胞中JAK 2/STAT 3的活化，而OSM刺激可以激活信号通路。
Oncostatin M (OSM) is a secreted cytokine mainly involved in chronic inflammatory and cardiovascular diseases through binding to OSM receptor β (OSMR-β). Recent studies demonstrated that the presence of OSM contributed to the destabilization of atherosclerotic plaque. To investigate whether OSMR-β deficiency affects atherosclerosis, male OSMR-β−/−ApoE−/− mice were generated and utilized. Here we observed that OSMR-β expression was remarkably upregulated in both human and mouse atherosclerotic lesions, which were mainly located in macrophages. We found that OSMR-β deficiency significantly ameliorated atherosclerotic burden in aorta and aortic root relative to ApoE-deficient littermates and enhanced the stability of atherosclerotic plaques by increasing collagen and smooth muscle cell content, while decreasing macrophage infiltration and lipid accumulation. Moreover, bone marrow transplantation of OSMR-β−/− hematopoietic cells to atherosclerosis-prone mice displayed a consistent phenotype. Additionally, we observed a relatively reduced level of JAK2 and signal transducer and activator of transcription (STAT)3 in vivo and under Ox-LDL stimulation in vitro. Our findings suggest that OSMR-β deficiency in macrophages improved high-fat diet-induced atherogenesis and plaque vulnerability. Mechanistically, the protective effect of OSMR-β deficiency on atherosclerosis may be partially attributed to the inhibition of the JAK2/STAT3 activation in macrophages, whereas OSM stimulation can activate the signaling pathway.