Department of Surgery, Division of Vascular Surgery, Stanford University School of Medicine, 300 Pasteur drive, Stanford, CA 94305, USA.
Stanford Cardiovascular Institute, Stanford University, 265 Campus Drive, Stanford, CA 94305, USA.
Cardiovasc Res. 2022 Oct 21;118(13):2792-2804. doi: 10.1093/cvr/cvab347.
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'.
Genome-wide sequencing studies, including 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, Activating transcription factor 3 (ATF3), 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 was 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 down-regulated in humans with advanced vascular disease.
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.
去分化和激活促炎途径是血管平滑肌细胞（SMC）在动脉粥样硬化发生过程中发生的关键转变。在这里，我们探讨了这种“动脉粥样硬化转变”的上游调节剂。
对来自动脉粥样硬化的小鼠 SMC 谱系示踪模型和人动脉粥样硬化病变中分离的细胞进行了全基因组测序研究，包括使用测序和 RNA-seq 的转座酶可及染色质测定法。在整体水平上，染色质可及性的改变与病变 SMC 的动脉粥样硬化转变有关，特别是与调节分化状态和补体依赖性炎症的基因有关。通过计算生物学，我们观察到先前与冠状动脉疾病相关的转录因子激活转录因子 3（ATF3）被预测为在转变过程中改变的基因的上游调节剂。在单细胞水平上，我们的结果表明，ATF3 是 SMC 向通过激活补体级联反应促进血管炎症的细胞亚群转变的关键抑制剂。人动脉粥样硬化病变中 SMC 中 ATF3 和补体成分 C3 的表达呈负相关，表明具有转化相关性。表型全基因组关联研究表明，导致 ATF3 表达减少的遗传变异与动脉粥样硬化风险增加相关，并且在患有晚期血管疾病的人中 ATF3 的表达明显下调。
我们的研究表明，动脉粥样硬化 SMC 的可塑性部分可以通过其染色质结构的动态变化来解释，这反过来可能导致其对炎症诱导的应激的适应性反应受损。
