Dynamic changes in chromatin accessibility are associated with the atherogenic transitioning of vascular smooth muscle cells.
Dynamic changes in chromatin accessibility are associated with the atherogenic transitioning of vascular smooth muscle cells.
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DOI：
10.1093/cvr/cvab347
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发表时间：
2021-11
影响因子：
10.8
通讯作者：
Ying Wang;Hua Gao;Fudi Wang;Zhongde Ye;M. Mokry;A. Turner;Jianqin Ye;Simon Koplev;Lingfeng Luo;T. Alsaigh;S. Adkar;Maria Elishaev;Xiaotang Gao;L. Maegdefessel;J. Björkegren;G. Pasterkamp;Clint L. Miller;E. Ross;N. Leeper
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作者：
Ying Wang;Hua Gao;Fudi Wang;Zhongde Ye;M. Mokry;A. Turner;Jianqin Ye;Simon Koplev;Lingfeng Luo;T. Alsaigh;S. Adkar;Maria Elishaev;Xiaotang Gao;L. Maegdefessel;J. Björkegren;G. Pasterkamp;Clint L. Miller;E. Ross;N. Leeper
去分化和促炎通路的激活是动脉粥样硬化形成过程中血管平滑肌细胞（SMC）的关键转变。在这里，我们探讨了这种“致动脉粥样硬化转变”的上游调节因子。方法和结果全基因组测序研究，包括ATAC-seq（使用测序的转座酶可降解染色质测定）和RNA-seq，对从动脉粥样硬化的小鼠SMC谱系追踪模型和人类动脉粥样硬化病变分离的细胞进行。在整体水平上，染色质可及性的改变与病变SMC的致动脉粥样硬化转变相关，特别是与控制分化状态和补体依赖性炎症的基因相关。使用计算生物学，我们观察到，以前与冠状动脉疾病相关的转录因子，ATF 3（激活转录因子3），被预测为在过渡期间改变的基因的上游调节因子。在单细胞水平，我们的研究结果表明，ATF 3是SMC向通过激活补体级联反应促进血管炎症的细胞亚群过渡的关键阻遏物。ATF 3和补体成分C3的表达在人动脉粥样硬化病变的SMC中呈负相关，提示翻译相关性。表型相关性研究表明，导致ATF 3表达减少的遗传变异与动脉粥样硬化风险增加相关，并且ATF 3的表达在患有晚期血管疾病的人中显著下调。结论动脉粥样硬化平滑肌细胞的可塑性可能与其染色质结构的动态变化有关，而染色质结构的动态变化又可能导致其对炎症诱导的应激反应不良。最近的CANTOS和COLCOT试验表明，靶向炎症通路可降低主要不良心血管事件的风险。然而，需要更具体的靶点来避免免疫抑制副作用。我们的数据确定了促炎SMC的上游调节因子ATF 3，其参与病变SMC的初始致动脉粥样硬化转变。恢复ATF 3活性可以防止SMC的去分化，并为抑制动脉粥样硬化病变中的补体依赖性炎症提供了一种新的翻译方法。
AIMS De-differentiation and activation of pro-inflammatory pathways are key transitions vascular smooth muscle cells (SMCs) make during atherogenesis. Here, we explored the upstream regulators of this 'atherogenic transition'. METHODS AND RESULTS Genome-wide sequencing studies, including ATAC-seq (Assay for Transposase-Accessible Chromatin using sequencing) and RNA-seq, were performed on cells isolated from both murine SMC-lineage tracing models of atherosclerosis and human atherosclerotic lesions. At the bulk level, alterations in chromatin accessibility were associated with the atherogenic transitioning of lesional SMCs, especially in relation to genes that govern differentiation status and complement-dependent inflammation. Using computational biology, we observed that a transcription factor previously related to coronary artery disease, ATF3 (Activating transcription factor 3), was predicted to be an upstream regulator of genes altered during the transition. At the single-cell level, our results indicated that ATF3 is a key repressor of SMC transitioning towards the subset of cells that promote vascular inflammation by activating the complement cascade. The expression of ATF3 and complement component C3 were negatively correlated in SMCs from human atherosclerotic lesions, suggesting translational relevance. Phenome-wide association studies indicated that genetic variation that results in reduced expression of ATF3 is correlated with an increased risk for atherosclerosis, and the expression of ATF3 was significantly downregulated in humans with advanced vascular disease. CONCLUSION Our study indicates that the plasticity of atherosclerotic SMCs may in part be explained by dynamic changes in their chromatin architecture, which in turn may contribute to their maladaptive response to inflammation-induced stress. TRANSLATIONAL PERSPECTIVE The recent CANTOS and COLCOT trials have shown that targeting inflammatory pathways lowers the risk of major adverse cardiovascular events. However, more specific targets are needed to avoid immunosuppressive side effects. Our data identify an upstream regulator of pro-inflammatory SMCs, ATF3, which is involved in the initial atherogenic transitioning of lesional SMCs. Restoring ATF3 activity may prevent the de-differentiation of SMCs and offer a novel translational approach for the suppression of complement-dependent inflammation in atherosclerotic lesions.