PRAS40 suppresses atherogenesis through inhibition of mTORC1-dependent pro-inflammatory signaling in endothelial cells
PRAS40 suppresses atherogenesis through inhibition of mTORC1-dependent pro-inflammatory signaling in endothelial cells
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DOI：
10.1038/s41598-019-53098-1
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发表时间：
2019-11
影响因子：
4.6
通讯作者：
K. S. Zhang;J. Schecker;A. Krull;Eva Riechert;L. Jürgensen;V. Kamuf-Schenk;Jana Burghaus;Leon Kiper;Thanh Cao Ho;Kerstin Wöltje;V. Stangl;H. Katus;K. Stangl;M. Völkers;Till F. Althoff
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文献类型：
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作者：
K. S. Zhang;J. Schecker;A. Krull;Eva Riechert;L. Jürgensen;V. Kamuf-Schenk;Jana Burghaus;Leon Kiper;Thanh Cao Ho;Kerstin Wöltje;V. Stangl;H. Katus;K. Stangl;M. Völkers;Till F. Althoff
内皮细胞的促炎激活在动脉粥样硬化中起着关键作用，许多促炎和致动脉粥样硬化的信号都集中在雷帕霉素的机制靶点（mTOR）上。在临床前研究中，mTOR复合物1（mTORC 1）的抑制剂减少了动脉粥样硬化，但包括胰岛素抵抗和血脂异常在内的副作用限制了它们在这种情况下的临床应用。因此，我们研究了PRAS 40，一种细胞类型特异性的mTORC 1内源性调节剂，作为替代靶点。事实上，我们以前发现PRAS 40基因治疗可以改善代谢状况;然而，其在内皮细胞中的功能及其在动脉粥样硬化中的作用仍然未知。在这里，我们发现PRAS 40负调节内皮mTORC 1和促炎信号。内皮细胞中PRAS 40的敲低促进TNFα诱导的mTORC 1信号传导、增殖、炎症标志物的上调和单核细胞募集。相反，PRAS 40过表达阻断了mTORC 1和所有促炎信号传导措施。这些作用通过使用torin 1的药理学mTORC 1抑制来模拟。在致动脉粥样硬化重塑的体内模型中，诱导内皮特异性PRAS 40缺陷的小鼠显示增强的内皮促炎活化以及增加的新生内膜增生和动脉粥样硬化病变形成。这些数据表明PRAS 40通过抑制内皮mTORC 1介导的促炎信号传导来抑制动脉粥样硬化。结合其对代谢稳态的有利作用，这使得PRAS 40成为治疗动脉粥样硬化的潜在靶标。
Endothelial pro-inflammatory activation plays a pivotal role in atherosclerosis, and many pro-inflammatory and atherogenic signals converge upon mechanistic target of rapamycin (mTOR). Inhibitors of mTOR complex 1 (mTORC1) reduced atherosclerosis in preclinical studies, but side effects including insulin resistance and dyslipidemia limit their clinical use in this context. Therefore, we investigated PRAS40, a cell type-specific endogenous modulator of mTORC1, as alternative target. Indeed, we previously found PRAS40 gene therapy to improve metabolic profile; however, its function in endothelial cells and its role in atherosclerosis remain unknown. Here we show that PRAS40 negatively regulates endothelial mTORC1 and pro-inflammatory signaling. Knockdown of PRAS40 in endothelial cells promoted TNFα-induced mTORC1 signaling, proliferation, upregulation of inflammatory markers and monocyte recruitment. In contrast, PRAS40-overexpression blocked mTORC1 and all measures of pro-inflammatory signaling. These effects were mimicked by pharmacological mTORC1-inhibition with torin1. In anin vivomodel of atherogenic remodeling, mice with induced endothelium-specific PRAS40 deficiency showed enhanced endothelial pro-inflammatory activation as well as increased neointimal hyperplasia and atherosclerotic lesion formation. These data indicate that PRAS40 suppresses atherosclerosis via inhibition of endothelial mTORC1-mediated pro-inflammatory signaling. In conjunction with its favourable effects on metabolic homeostasis, this renders PRAS40 a potential target for the treatment of atherosclerosis.