Department of Cardiology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, China.
College of Second Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China.
Front Immunol. 2022 Feb 22;13:817572. doi: 10.3389/fimmu.2022.817572. eCollection 2022.
Inflammation is an important driver of atherosclerosis. Succinate is a new extracellular inflammatory alarm released by activated macrophages. Succinate is sensed by succinate receptor 1 (Sucnr1) and then transferred to effector cells. It is worth exploring whether succinate is capable of facilitating the inflammatory response in atherosclerosis. In this study, we firstly found that arterial serum of Coronary Heart Disease (CHD) patients contained significantly higher succinate and interleukin (IL)-1β than Health control (HC) subjects, and succinate was positively correlated with IL-1β. As demonstrated by the study, succinate/hypoxia-inducible factor 1α (Hif)-1α/IL-1β signal axis existed and significantly facilitated the inflammatory program in human umbilical vein endothelial cells (HUVECs). Under the coculture, activated macrophages released succinate, which would be transferred to HUVECs Sucnr1 and then activate Hif-1α to produce a greater amount of IL-1β. Likewise, the aortic sinus's inflammatory phenotype was found to be more significant within Apoe mice that were injected with succinate. Furthermore, Sucnr1 inhibitor (NF-56-EJ40) could significantly interrupt succinate/IL-1β signal in HUVECs and macrophages. As revealed by this study, glycolytic metabolism following the release of succinate could be found in atherosclerotic pathology, and succinate would drive succinate/IL-1β signal dependent on Sucnr1 and then exacerbate inflammatory responses. Sucnr1 might be a novel target for cutting off the transduction of succinate signal to prevent the inflammation of atherosclerosis.
炎症是动脉粥样硬化的一个重要驱动因素。琥珀酸是一种由活化的巨噬细胞释放的新型细胞外炎症警报分子。琥珀酸通过琥珀酸受体 1（Sucnr1）被感知，然后传递到效应细胞。值得探讨的是，琥珀酸是否能够促进动脉粥样硬化中的炎症反应。在这项研究中，我们首先发现冠心病（CHD）患者的动脉血清中含有明显高于健康对照组（HC）的琥珀酸和白细胞介素（IL）-1β，并且琥珀酸与 IL-1β呈正相关。正如研究所示，存在琥珀酸/低氧诱导因子 1α（Hif）-1α/IL-1β信号轴，并且它可以显著促进人脐静脉内皮细胞（HUVECs）的炎症程序。在共培养物中，活化的巨噬细胞释放琥珀酸，琥珀酸会被转移到 HUVECs 的 Sucnr1 上，然后激活 Hif-1α 产生更多的 IL-1β。同样，在注射琥珀酸的 Apoe 小鼠中，主动脉窦的炎症表型更为明显。此外，Sucnr1 抑制剂（NF-56-EJ40）可以显著中断 HUVECs 和巨噬细胞中的琥珀酸/IL-1β信号。这项研究表明，在动脉粥样硬化病理中可以发现琥珀酸释放后的糖酵解代谢，琥珀酸通过 Sucnr1 驱动琥珀酸/IL-1β信号，从而加剧炎症反应。Sucnr1 可能是阻断琥珀酸信号转导以防止动脉粥样硬化炎症的新靶点。
