Pim-2 kinase inhibits inflammation by suppressing the mTORC1 pathway in atherosclerosis.
Pim-2 kinase inhibits inflammation by suppressing the mTORC1 pathway in atherosclerosis.
复制标题
Pim-2 激酶通过抑制动脉粥样硬化中的 mTORC1 通路来抑制炎症
DOI：
10.18632/aging.203547
复制
发表时间：
2021-09-21
期刊：
影响因子：
--
通讯作者：
Cheng X
中科院分区：
文献类型：
--
作者：
Liao M;Hu F;Qiu Z;Li J;Huang C;Xu Y;Cheng X
背景：炎症免疫学说在动脉粥样硬化的发病机制中引起了广泛关注。小鼠Pim-2激酶的前病毒整合位点在凋亡途径和抗炎反应中发挥作用。在这里，我们研究了Pim-2激酶是否通过抑制mTORC 1通路来抑制动脉粥样硬化炎症。方法：采用高脂饲料喂养ApoE -/-小鼠建立动脉粥样硬化动物模型。THP-1衍生的巨噬细胞在体外经受ox-LDL（50 μg/ml，24小时）条件以模拟体内条件。结果：ox-LDL处理的THP-1源性巨噬细胞和动脉粥样硬化小鼠模型中Pim-2蛋白表达上调。此外，ox-LDL还可上调THP-1源性巨噬细胞p-mTOR、p-S6 K1和p-4 EBP 1、细胞内脂滴、游离胆固醇和胆固醇酯的蛋白表达以及炎症细胞因子IL-6、MCP-1、TLR-4和TNF-α的mRNA表达。在功能上，过表达的Pim-2（Pim-2 OE）在体外和体内减弱与mTORC 1信号通路相关的动脉粥样硬化炎症，而敲低的Pim-2（Pim-2 KD）显著促进与mTORC 1信号通路上调相关的动脉粥样硬化炎症。ApoE -/-小鼠经Pim-2 OE处理后，主动脉和主动脉根部的斑块面积和病变程度减轻，而经Pim-2 KD处理后，斑块面积和病变程度加重。此外，mTOR激动剂（MHY 1485）在Pim-2 OE后抵消了Pim-2在ox-LDL处理的THP-1衍生的巨噬细胞中的抗炎作用，而雷帕霉素在Pim-2 KD后挽救了ox-LDL处理的THP-1衍生的巨噬细胞中的动脉粥样硬化炎症。此外，si-mTOR和si-Raptor在Pim-2 KD的背景下减轻ox-LDL处理的THP-1衍生的巨噬细胞中的动脉粥样硬化促炎作用。结论：Pim-2激酶通过抑制mTORC 1通路抑制动脉粥样硬化炎症反应。
Background: Inflammatory immunity theory has raised considerable concern in the pathogenesis of atherosclerosis. Proviral integration site of murine 2 (Pim-2) kinases functions in apoptosis pathways and the anti-inflammatory response. Here, we investigated whether Pim-2 kinase inhibits atherosclerotic inflammation by suppressing the mTORC1 pathway. Methods: An atherosclerosis animal model was established by feeding ApoE -/- mice a high-fat diet. THP-1-derived macrophages were subjected to ox-LDL (50 μg/ml, 24h) conditions in vitro to mimic the in vivo conditions. Result: The protein expression of Pim-2 was upregulated in ox-LDL-treated THP-1-derived macrophages and an atherosclerotic mouse model. Additionally, ox-LDL upregulated the protein expression of p-mTOR, p-S6K1 and p-4EBP1, intracellular lipid droplets, free cholesterol and cholesterylester and the mRNA expression of inflammatory cytokines, including IL-6, MCP-1, TLR-4 and TNF-α, in THP-1-derived macrophages. Functionally, overexpressed Pim-2 (Pim-2 OE) attenuated atherosclerotic inflammation associated with the mTORC1 signaling pathway in vitro and in vivo, whereas knocked down Pim-2 (Pim-2 KD) markedly promoted atherosclerotic inflammation associated with upregulation of the mTORC1 signaling pathway. The plaque areas and lesions in the whole aorta and aortic root sections were alleviated in ApoE -/- mice with Pim-2 OE, but aggravated by Pim-2 KD. Additionally, an mTOR agonist (MHY1485) counteracted the anti-inflammatory effect of Pim-2 in ox-LDL-treated THP-1-derived macrophages after Pim-2 OE, whereas rapamycin rescued atherosclerotic inflammation in ox-LDL-treated THP-1-derived macrophages after Pim-2 KD. Furthermore, si-mTOR and si-Raptor alleviated the atherosclerotic proinflammatory effect in ox-LDL-treated THP-1-derived macrophages in a the background of Pim-2 KD. Conclusions:These results indicated that Pim-2 kinase inhibits atherosclerotic inflammation by suppressing the mTORC1 pathway.
登录
查看更多内容
DOI：
10.1161/circinterventions.118.007283
发表时间：
2019-06-01
影响因子：
5.6
作者：
Chevalier, Bernard;Abizaid, Alexandre;Stone, Gregg W.
通讯作者：
Stone, Gregg W.
影响因子：
4.6
作者：
Jiménez-García MP;Lucena-Cacace A;Robles-Frías MJ;Narlik-Grassow M;Blanco-Aparicio C;Carnero A
通讯作者：
Carnero A
影响因子：
20.3
作者：
Lu, Jing;Zavorotinskaya, Tatiana;Garcia, Pablo D.
通讯作者：
Garcia, Pablo D.
影响因子：
11.3
作者：
Abizaid, Alexandre;Carrie, Didier;Stone, Gregg W.
通讯作者：
Stone, Gregg W.
影响因子：
5
作者：
Kiyan, Yulia;Tkachuk, Sergey;Dumler, Inna
通讯作者：
Dumler, Inna