■血管平滑肌细胞(VSMC)是主动脉中层的主要细胞类型,在主动脉疾病中起关键作用。先天免疫是心血管疾病的主要驱动力。
■为了确定先天免疫在VSMC和主动脉病变中的作用,我们对ApoE-/-血管紧张素II(AngII)诱导的主动脉瘤(AAA)时程的主动脉进行了转录组分析,和ApoE-/-动脉粥样硬化时间进程,以及与危险相关的分子模式(DAMPs)刺激的VSMC。
■我们取得了重要发现:1)95%和45%的先天免疫途径上调(UIIP,根据1226个先天性免疫基因的数据)在ApoE-/-AngII诱导的AAA在7天与14天和28天不同,AAA分别显示UIIP的双峰,主峰在7天,次峰在28天;2)ApoE-/-动脉粥样硬化中的所有UIIP在6周时与32周和78周不同(两波);3)分析了另外12个具有1325个细胞因子和趋化因子基因的先天免疫相关基因列表,2022血浆膜蛋白基因,373个分化(CD)标记基因簇,280个核膜蛋白基因,1425个核仁蛋白基因,6750个核质蛋白基因,1496个转录因子(TFs),包括15个先驱TFs,164种组蛋白修饰酶,102个氧化细胞死亡基因,68个坏死细胞死亡基因,和47个外渗基因证实了动脉粥样硬化中的两波炎症和AAA中的双峰炎症;4)DAMPs刺激的VSMC是先天免疫细胞,根据先天免疫基因和来自12个其他列表的基因的上调判断;5)DAMPs刺激的VSMC不仅通过上调7种VSMC塑料细胞类型的82个标志物中的一些来增加转分化潜力,包括成纤维细胞,成骨,成肌纤维细胞,巨噬细胞,脂肪细胞,泡沫细胞,和间充质细胞,而且还有18种新的细胞类型(79种人类细胞类型中具有8065种细胞标记);6)基因缺陷转录组的分析表明抗氧化剂转录因子NRF2抑制,然而,其他五个炎症转录因子和主调节因子,包括AHR,NF-KB,NOX(ROS酶),PERK,SET7促进动脉粥样硬化中12个先天免疫基因的上调,AAA,和DAMP刺激的VSMC;7)SET7和经过训练的促进耐受性的代谢物衣康酸酯均有助于AAA中细胞因子的双峰上调。
■我们的发现为先天免疫反应和核应激在AAA发展中的作用提供了新的见解。动脉粥样硬化,和VSMC免疫学,并为治疗这些重要的心血管和脑血管疾病提供了新的治疗靶点。
Vascular smooth muscle cells (VSMCs) are the predominant cell type in the medial layer of the aorta, which plays a critical role in aortic diseases. Innate immunity is the main driving force for cardiovascular diseases.
To determine the roles of innate immunity in VSMC and aortic pathologies, we performed transcriptome analyses on aortas from ApoE-/- angiotensin II (Ang II)-induced aortic aneurysm (AAA) time course, and ApoE-/- atherosclerosis time course, as well as VSMCs stimulated with danger-associated molecular patterns (DAMPs).
We made significant findings: 1) 95% and 45% of the upregulated innate immune pathways (UIIPs, based on data of 1226 innate immune genes) in ApoE-/- Ang II-induced AAA at 7 days were different from that of 14 and 28 days, respectively; and AAA showed twin peaks of UIIPs with a major peak at 7 days and a minor peak at 28 days; 2) all the UIIPs in ApoE-/- atherosclerosis at 6 weeks were different from that of 32 and 78 weeks (two waves); 3) analyses of additional 12 lists of innate immune-related genes with 1325 cytokine and chemokine genes, 2022 plasma membrane protein genes, 373 clusters of differentiation (CD) marker genes, 280 nuclear membrane protein genes, 1425 nucleoli protein genes, 6750 nucleoplasm protein genes, 1496 transcription factors (TFs) including 15 pioneer TFs, 164 histone modification enzymes, 102 oxidative cell death genes, 68 necrotic cell death genes, and 47 efferocytosis genes confirmed two-wave inflammation in atherosclerosis and twin-peak inflammation in AAA; 4) DAMPs-stimulated VSMCs were innate immune cells as judged by the upregulation of innate immune genes and genes from 12 additional lists; 5) DAMPs-stimulated VSMCs increased trans-differentiation potential by upregulating not only some of 82 markers of 7 VSMC-plastic cell types, including fibroblast, osteogenic, myofibroblast, macrophage, adipocyte, foam cell, and mesenchymal cell, but also 18 new cell types (out of 79 human cell types with 8065 cell markers); 6) analysis of gene deficient transcriptomes indicated that the antioxidant transcription factor NRF2 suppresses, however, the other five inflammatory transcription factors and master regulators, including AHR, NF-KB, NOX (ROS enzyme), PERK, and SET7 promote the upregulation of twelve lists of innate immune genes in atherosclerosis, AAA, and DAMP-stimulated VSMCs; and 7) both SET7 and trained tolerance-promoting metabolite itaconate contributed to twin-peak upregulation of cytokines in AAA.
Our findings have provided novel insights on the roles of innate immune responses and nuclear stresses in the development of AAA, atherosclerosis, and VSMC immunology and provided novel therapeutic targets for treating those significant cardiovascular and cerebrovascular diseases.