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1.
Front Immunol ; 14: 1268916, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37731512

RESUMO

To determine the roles of endoplasmic reticulum (ER) stress and trained immunity, we performed transcriptome analyses on the thoracic aorta (TA) and abdominal aorta (AA) from the angiotensin II (Ang II)-HFD-ApoE-KO aneurysm model and made significant findings: 1) Ang II bypassed HFD-induced metabolic reprogramming and induced stronger inflammation in AA than in TA; 2) Ang II and HFD upregulated 890 genes in AA versus TA and induced cytokine signaling; 3) Ang II AA and TA upregulated 73 and 68 cytokines, scRNA-Seq identified markers of macrophages and immune cells, cell death regulators, respectively; transdifferentiation markers of neuron, glial, and squamous epithelial cells were upregulated by Ang II-AA and TA; and pyroptosis signaling with IL-1ß and caspase-4 were more upregulated in Ang II-AA than in TA; 4) Six upregulated transcriptomes in patients with AAA, Ang II AA, Ang II TA, additional aneurysm models, PPE-AAA and BAPN-Ang II-AAA, were partially overlapped with 10 lists of new ER stress gene sets including 3 interaction protein lists of ER stress regulators ATF6, PERK, and IRE1, HPA ER localization genes, KEGG signal genes, XBP1 transcription targets, ATF4 (PERK) targets, ATF6 targets, thapsigargin ER stress genes, tunicamycin-ER stress genes, respectively; 5) Ang II-AA and TA upregulated ROS regulators, MitoCarta genes, trained immunity genes, and glycolysis genes; and 6) Gene KO transcriptomes indicated that ATF6 and PERK played more significant roles than IRE1 in promoting AAA and trained immunity whereas antioxidant NRF2 inhibited them. Our unprecedented ER-focused transcriptomic analyses have provided novel insights on the roles of ER as an immune organelle in sensing various DAMPs and initiating ER stress that triggers Ang II-accelerated trained immunity and differs susceptibilities of thoracic and abdominal aortas to diseases.


Assuntos
Aneurisma , Aorta Abdominal , Humanos , Angiotensina II/farmacologia , Suscetibilidade a Doenças , Imunidade Inata , Proteínas Serina-Treonina Quinases
2.
Front Immunol ; 14: 1348238, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38327764

RESUMO

Introduction: 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. Methods: 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). Results: 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. Discussion: 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.


Assuntos
Aneurisma da Aorta Abdominal , Aneurisma Aórtico , Aterosclerose , Humanos , Músculo Liso Vascular/metabolismo , Aneurisma da Aorta Abdominal/metabolismo , Inflamação/metabolismo , NF-kappa B/metabolismo , Imunidade Inata , Transdiferenciação Celular , Aterosclerose/metabolismo , Apolipoproteínas E/genética
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