Ying Wang1,2, Hua Gao1,2, Fudi Wang1,2, Zhongde Ye1,2, Michal Mokry3, Adam W Turner4, Jianqin Ye1, Simon Koplev5, Lingfeng Luo1,2, Tom Alsaigh1,6, Shaunak S Adkar1, Maria Elishaev7, Xiangyu Gao7, Lars Maegdefessel8,9, Johan L M Björkegren10, Gerard Pasterkamp3, Clint L Miller4, Elsie G Ross1,2, Nicholas J Leeper1,2. 1. Department of Surgery, Division of Vascular Surgery, Stanford University School of Medicine, 300 Pasteur drive, Stanford, CA 94305, USA. 2. Stanford Cardiovascular Institute, Stanford University, 265 Campus Drive, Stanford, CA 94305, USA. 3. Department of Cardiology and Laboratory of Clinical Chemistry, University Medical Center Utrecht, Heidelberglaan 100, Utrecht 3584 CX, the Netherlands. 4. Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, 1335 Lee St, Charlottesville, VA 22908, USA. 5. Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK. 6. Department of Cardiovascular Medicine, Stanford University School of Medicine, 870 Quarry Road Extension, Stanford, CA 94305, USA. 7. Department of Pathology and Laboratory Medicine, Centre for Heart Lung Innvoation, University of British Columbia, 166-1081 Burrard St, Vancouver, BC V6Z 1Y6, Canada. 8. Department for Vascular and Endovascular Surgery, Klinikum rechts der Isar, Technical University Munich, and the German Center for Cardiovascular Research (DZHK partner site), Biedersteiner Str. 29, Munich 80802, Germany. 9. Department of Internal Medicine, Center for Molecular Medicine, Karolinska Institute, Visionsgatan 18, Stockholm 171 76, Sweden. 10. Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave, New York, NY 10029, USA.
Abstract
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 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. 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. Published on behalf of the European Society of Cardiology. All rights reserved.
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 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. 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. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Maria Elishaev; Chani J Hodonsky; Saikat Kumar B Ghosh; Aloke V Finn; Moritz von Scheidt; Ying Wang Journal: Front Cardiovasc Med Date: 2022-07-07