A Nrf2-OSGIN1&2-HSP70 axis mediates cigarette smoke-induced endothelial detachment: implications for plaque erosion.
A Nrf2-OSGIN1&2-HSP70 axis mediates cigarette smoke-induced endothelial detachment: implications for plaque erosion.
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DOI：
10.1093/cvr/cvad022
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发表时间：
2023-08-07
影响因子：
10.8
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中科院分区：
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约 30% 的急性冠脉综合征 (ACS) 是由斑块内皮侵蚀引起的。吸烟是斑块侵蚀的危险因素，斑块侵蚀最常发生在斑块的上游表面，那里的内皮承受较高的剪切应力。我们试图在体外重现这些条件，以确定可能与斑块侵蚀相关的潜在病理机制。在高流量（7.5 Pa 剪切应力）下培养人冠状动脉内皮细胞 (HCAEC)，并长期将其暴露于香烟烟雾提取物 (CSE) 和肿瘤坏死因子-α (TNFα) 中，重现了 HCAEC 粘附缺陷，这与 Nrf2 调节的基因表达增强相对应。 Nrf2 的药理学激活或腺病毒过度表达引发内皮脱离，确定 Nrf2 是内皮脱离的介质。在该模型中，生长/分化因子 15 (GDF15) 表达升高，与斑块破裂患者相比，经历斑块侵蚀的患者血浆中的蛋白质表达升高。在升高的流量下，CSE 和 TNFα 增加了两个 Nrf2 调节基因 OSGIN1 和 OSGIN2 的表达，并且在体内暴露于香烟烟雾的小鼠的主动脉中表达也升高。 OSGIN1&2 的敲低抑制了 Nrf2 诱导的细胞脱离。 OSGIN1&2的过度表达诱导内皮脱离并导致细胞周期停滞、诱导衰老、粘着斑和肌动蛋白应激纤维的丧失，以及部分由HSP70介导的蛋白质稳态紊乱，其恢复减少了HCAEC脱离。在吸烟的 ACS 患者中，与斑块破裂相比，斑块侵蚀时 HSP70 的血液浓度升高。我们确定了一种新的 Nrf2-OSGIN1&2-HSP70 轴，可以调节内皮粘附，升高的 GDF15 和 HSP70 作为吸烟患者斑块侵蚀的生物标志物，以及两个有可能降低斑块侵蚀风险的治疗靶点。血流量升高、香烟烟雾提取物和 TNFα 可以引发内皮脱离，从而复制患者斑块侵蚀的特征。 Nrf2 激活或 OSGIN1&2 过度表达可能通过分子伴侣介导的自噬失调诱导人冠状动脉内皮细胞脱离，这可以通过抑制 HSP70 和 5' AMP 激活的蛋白激酶激活来挽救。
Endothelial erosion of plaques is responsible for ∼30% of acute coronary syndromes (ACS). Smoking is a risk factor for plaque erosion, which most frequently occurs on the upstream surface of plaques where the endothelium experiences elevated shear stress. We sought to recreate these conditions in vitro to identify potential pathological mechanisms that might be of relevance to plaque erosion. Culturing human coronary artery endothelial cells (HCAECs) under elevated flow (shear stress of 7.5 Pa) and chronically exposing them to cigarette smoke extract (CSE) and tumour necrosis factor-alpha (TNFα) recapitulated a defect in HCAEC adhesion, which corresponded with augmented Nrf2-regulated gene expression. Pharmacological activation or adenoviral overexpression of Nrf2 triggered endothelial detachment, identifying Nrf2 as a mediator of endothelial detachment. Growth/Differentiation Factor-15 (GDF15) expression was elevated in this model, with protein expression elevated in the plasma of patients experiencing plaque erosion compared with plaque rupture. The expression of two Nrf2-regulated genes, OSGIN1 and OSGIN2, was increased by CSE and TNFα under elevated flow and was also elevated in the aortas of mice exposed to cigarette smoke in vivo. Knockdown of OSGIN1&2 inhibited Nrf2-induced cell detachment. Overexpression of OSGIN1&2 induced endothelial detachment and resulted in cell cycle arrest, induction of senescence, loss of focal adhesions and actin stress fibres, and disturbed proteostasis mediated in part by HSP70, restoration of which reduced HCAEC detachment. In ACS patients who smoked, blood concentrations of HSP70 were elevated in plaque erosion compared with plaque rupture. We identified a novel Nrf2-OSGIN1&2-HSP70 axis that regulates endothelial adhesion, elevated GDF15 and HSP70 as biomarkers for plaque erosion in patients who smoke, and two therapeutic targets that offer the potential for reducing the risk of plaque erosion. Elevated flow, cigarette smoke extract, and TNFα can trigger endothelial detachment, replicating features of plaque erosion in patients. Nrf2 activation or overexpression of OSGIN1&2 induces detachment of human coronary artery endothelial cells, likely through dysregulation of chaperone-mediated autophagy, that can be rescued by inhibition of HSP70 and 5′ AMP-activated protein kinase activation.
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影响因子：
4.8
作者：
Chen, XL;Varner, SE;Kunsch, C
通讯作者：
Kunsch, C
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作者：
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通讯作者：
Tremoli, Elena
影响因子：
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作者：
Jia, Haibo;Abtahian, Farhad;Aguirre, Aaron D.;Lee, Stephen;Chia, Stanley;Lowe, Harry;Kato, Koji;Yonetsu, Taishi;Vergallo, Rocco;Hu, Sining;Tian, Jinwei;Lee, Hang;Park, Seung-Jung;Jang, Yang-Soo;Raffel, Owen C.;Mizuno, Kyoichi;Uemura, Shiro;Itoh, Tomonori;Kakuta, Tsunekazu;Choi, So-Yeon;Dauerman, Harold L.;Prasad, Abhiram;Toma, Catalin;McNulty, Iris;Zhang, Shaosong;Yu, Bo;Fuster, Valentine;Narula, Jagat;Virmani, Renu;Jang, Ik-Kyung
通讯作者：
Jang, Ik-Kyung