AIP1 suppresses atherosclerosis by limiting hyperlipidemia-induced inflammation and vascular endothelial dysfunction.
AIP1 suppresses atherosclerosis by limiting hyperlipidemia-induced inflammation and vascular endothelial dysfunction.
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DOI：
10.1161/atvbaha.113.301220
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发表时间：
2013-04
期刊：
影响因子：
--
通讯作者：
Min W
中科院分区：
文献类型：
--
作者：
Huang Q;Qin L;Dai S;Zhang H;Pasula S;Zhou H;Chen H;Min W
凋亡信号调节激酶 1 (ASK1) 相互作用蛋白 1 (AIP1) 是一种信号转接分子，与促炎介质诱导的应激和凋亡信号传导有关。然而，其在动脉粥样硬化中的作用尚未确定。在本研究中，我们使用AIP1缺失（AIP1−/−）小鼠来检查其对ApoE缺失（ApoE−/−）小鼠动脉粥样硬化模型中动脉粥样硬化病变的影响。 ApoE−/−对照小鼠在接受西式饮食10周后，主动脉根部和降主动脉出现动脉粥样硬化，而ApoE−/−AIP1−/−双敲除（DKO）小鼠的动脉粥样硬化病变明显加重。 DKO 小鼠血浆炎症细胞因子增加，但体重、总胆固醇水平或脂蛋白谱没有显着变化。 DKO 小鼠的主动脉显示炎症增加和内皮细胞 (EC) 功能障碍与 NF-κB 活性相关，这与病变区域巨噬细胞积累的增加相关。重要的是，当将来自 DKO 供体的巨噬细胞转移至 ApoE-KO 受体时，不足以增强炎症反应和动脉粥样硬化形成。机制研究表明，AIP1 在主动脉 EC 中高表达，但在巨噬细胞中不表达，EC 中 AIP1 缺失显着增强氧化 LDL 诱导的 NF-κB 信号传导、炎症分子的基因表达和单核细胞粘附，表明血管 EC 是 DKO 小鼠中观察到的炎症反应增加的原因。我们的数据表明，主动脉 EC 中 AIP1 的缺失主要导致 ApoE−/−AIP1−/− 小鼠中病变扩展加剧，揭示了 AIP1 在限制炎症、EC 功能障碍和动脉粥样硬化中的重要作用。
Apoptosis signal-regulating kinase 1 (ASK1)–interacting protein-1 (AIP1) is a signaling adaptor molecule implicated in stress and apoptotic signaling induced by proinflammatory mediators. However, its function in atherosclerosis has not been established. In the present study, we use AIP1-null (AIP1−/−) mice to examine its effect on atherosclerotic lesions in an ApoE-null (ApoE−/−) mouse model of atherosclerosis. ApoE−/− control mice developed atherosclerosis in the aortic roots and descending aortas upon Western-type diet for 10 weeks, while the atherosclerotic lesions are significantly augmented in ApoE−/−AIP1−/− double knockout (DKO) mice. DKO mice show increases in plasma inflammatory cytokines with no significant alterations in body weight, total cholesterol levels or lipoprotein profiles. Aortas in DKO mice show increased inflammation and endothelial cell (EC) dysfunction with NF-κB activity, correlating with increased accumulation of macrophages in the lesion area. Importantly, macrophages from DKO donors are not sufficient to augment inflammatory responses and atherogenesis when transferred to ApoE-KO recipients. Mechanistic studies suggest that AIP1 is highly expressed in aortic EC but not in macrophages, and AIP1 deletion in EC significantly enhance oxidized LDL-induced NF-κB signaling, gene expression of inflammatory molecules and monocyte adhesion, suggesting that vascular EC are responsible for the increased inflammatory responses observed in DKO mice. Our data demonstrate that loss of AIP1 in aortic EC primarily contributes to the exacerbated lesion expansion in the ApoE−/−AIP1−/− mice, revealing an important role of AIP1 in limiting inflammation, EC dysfunction and atherosclerosis.