Substitution of the SERCA2 Cys674 reactive thiol accelerates atherosclerosis by inducing endoplasmic reticulum stress and inflammation
Substitution of the SERCA2 Cys674 reactive thiol accelerates atherosclerosis by inducing endoplasmic reticulum stress and inflammation
复制标题
SERCA2 Cys(674) 反应性硫醇的替代通过诱导内质网应激和炎症加速动脉粥样硬化
DOI：
10.1111/bph.15912
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发表时间：
2022-07-21
影响因子：
7.3
通讯作者：
Tong，Xiaoyong
中科院分区：
文献类型：
--
作者：
Su，Hang;Mei，Yu;Tong，Xiaoyong
背景与目的肌浆网/内质网Ca ~（2+）ATP酶2的半胱氨酸674（C674）巯基在动脉粥样硬化状态下易被不可逆氧化。然而，C674硫醇氧化还原状态在动脉粥样硬化发展中的作用仍不清楚。我们的目标是阐明可能的机制。实验方法杂合子SERCA 2 C674 S敲入小鼠，其中一半的C674被丝氨酸取代（S674），用于模拟在病理条件下发生的反应性C674硫醇的去除。使用骨髓源性巨噬细胞（BMDM）和心脏内皮细胞（EC）进行细胞内Ca 2+、巨噬细胞粘附和蛋白表达分析。分离整个主动脉和主动脉根进行组织学analysis.Key ResultsCell培养研究表明，SERCA 2 C674的部分取代增加细胞内Ca 2+水平和诱导ER应力在BMDM和EC。促炎因子的释放和巨噬细胞粘附在SKI BMDM中增加。在EC中，S674的过表达诱导内皮炎症并促进巨噬细胞募集。SKI小鼠出现更严重的动脉粥样硬化斑块和巨噬细胞积聚。此外，4-苯基丁酸，ER应激抑制剂，抑制ER应激和炎症反应的BMDM和EC，并减轻动脉粥样硬化在SKI mice.Conclusions and ImplicationsThe取代SERCA 2 C674硫醇加速动脉粥样硬化的发展，诱导ER应激和炎症。我们的研究结果强调了SERCA 2 C674氧化还原状态在动脉粥样硬化背景下的重要性，并开辟了一种新的治疗策略来对抗动脉粥样硬化。
Background and PurposeThe cysteine674(C674) thiol of sarcoplasmic/endoplasmic reticulum Ca2+ATPase 2 is easily and irreversibly oxidized under atherosclerotic conditions. However, the contribution of the C674 thiol redox status in the development of atherosclerosis remains unclear. Our goal was to elucidate the possible mechanism involved.Experimental ApproachHeterozygous SERCA2 C674S knock‐in mice in which half of the C674 was substituted by serine (S674) were used to mimic the removal of the reactive C674 thiol, which occurs under pathological conditions. Bone marrow‐derived macrophages (BMDMs) and cardiac endothelial cells (ECs) were used for intracellular Ca2+, macrophage adhesion, and protein expression analysis. The whole aorta and aortic root were isolated for histological analysis.Key ResultsCell culture studies suggest the partial substitution of SERCA2 C674 increased intracellular Ca2+levels and induced ER stress in both BMDMs and ECs. The release of proinflammatory factors and macrophage adhesion increased in SKI BMDMs. In ECs, overexpression of S674 induced endothelial inflammation and promoted macrophage recruitment. SKI mice developed more severe atherosclerotic plaque and macrophage accumulation. Additionally, 4‐phenyl butyric acid, an ER stress inhibitor, suppressed ER stress and inflammatory responses in BMDMs and ECs, and alleviated atherosclerosis in SKI mice.Conclusions and ImplicationsThe substitution of SERCA2 C674 thiol accelerates the development of atherosclerosis by inducing ER stress and inflammation. Our findings highlight the importance of SERCA2 C674 redox state in the context of atherosclerosis and open up a novel therapeutic strategy to combat atherosclerosis.