Epac1 (Exchange Protein Directly Activated by cAMP 1) Upregulates LOX-1 (Oxidized Low-Density Lipoprotein Receptor 1) to Promote Foam Cell Formation and Atherosclerosis Development.
Epac1 (Exchange Protein Directly Activated by cAMP 1) Upregulates LOX-1 (Oxidized Low-Density Lipoprotein Receptor 1) to Promote Foam Cell Formation and Atherosclerosis Development.
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DOI：
10.1161/atvbaha.119.314238
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发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Cheng X
中科院分区：
文献类型：
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作者：
Robichaux WG 3rd;Mei FC;Yang W;Wang H;Sun H;Zhou Z;Milewicz DM;Teng BB;Cheng X
cAMP第二信使系统是一条重要的应激反应途径，在心血管系统的正常功能和心脏病的发病机制中起重要作用。在这里，我们测试的假设，交换蛋白直接激活cAMP 1（Epac 1）作为一个主要的下游效应cAMP信号，以促进动脉粥样硬化的发生，并代表一个新的治疗靶点。为了确定Epac 1在动脉粥样硬化发展中的功能，通过将Epac 1 −/−小鼠与缺乏Ldlr和Apobec 1的动脉粥样硬化倾向LDb小鼠杂交来产生三重敲除小鼠模型（LTe）。与LDb同窝仔相比，LTe动物中Epac 1的缺失导致通过死后染色测量的动脉粥样硬化病变形成显著减少，伴随着通过免疫荧光染色确定的动脉粥样硬化斑块内巨噬细胞/泡沫细胞浸润减弱。原代骨髓源性巨噬细胞（BMDM）从Epac 1-null和野生型小鼠中分离，以研究Epac 1在脂质摄取和泡沫细胞形成中的作用。氧化低密度脂蛋白（ox-LDL）刺激BMDM导致细胞内cAMP和Epac 1水平升高，而Epac特异性激动剂，增加野生型中的脂质积累，但不是Epac 1无效的BMDM。Epac 1通过PKC上调氧化型低密度脂蛋白受体1（LOX-1）（ox-LDL摄取的主要清道夫受体），与ox-LDL发挥前馈机制，增加脂质摄取并推动泡沫细胞形成和动脉粥样硬化形成。我们的研究表明cAMP/Epac 1信号在动脉粥样硬化病变发展过程中通过促进ox-LDL摄取和泡沫细胞形成在血管重塑中发挥重要作用。因此，Epac 1代表了动脉粥样硬化的一个有前途的、未开发的治疗靶点。
The cAMP second messenger system, a major stress-response pathway, play essential roles in normal cardiovascular functions and in pathogenesis of heart diseases. Herein, we test the hypothesis that the exchange protein directly activated by cAMP 1 (Epac1) acts as a major down-stream effector of cAMP signaling to promote atherogenesis and represents a novel therapeutic target. To ascertain Epac1’s function in atherosclerosis development, a triple knockout mouse model (LTe) was generated by crossing Epac1−/− mice with atherosclerosis-prone LDb mice lacking both Ldlr and Apobec1. Deletion of Epac1 led to a significant reduction of atherosclerotic lesion formation as measured by post-mortem staining, accompanied by attenuated macrophage/foam cell infiltrations within atherosclerotic plaques as determined by immunofluorescence staining in LTe animals compared to LDb littermates. Primary bone-marrow derived macrophages (BMDM) were isolated from Epac1-null and wild type mice to investigate the role of Epac1 in lipid uptake and foam cell formation. Oxidized-LDL (ox-LDL) stimulation of BMDMs led to elevated intracellular cAMP and Epac1 levels, whereas an Epac-specific agonist, increased lipid accumulation in wild type, but not Epac1-null BMDMs. Mechanistically, Epac1 acts through PKC to upregulate oxidized low-density lipoprotein receptor 1 (LOX-1), a major scavenger receptor for ox-LDL uptake, exerting a feedforward mechanism with ox-LDL to increase lipid uptake and propel foam cell formation and atherogenesis. Our study demonstrates a fundamental role of cAMP/Epac1 signaling in vascular remodeling by promoting ox-LDL uptake and foam cell formation during atherosclerosis lesion development. Therefore, Epac1 represents a promising, unexplored therapeutic target for atherosclerosis.