Single‐cell RNA sequencing reveals a mechanism underlying the susceptibility of the left atrial appendage to intracardiac thrombogenesis during atrial fibrillation
Abstract Background Atrial fibrillation (AF) is associated with an increased risk of thrombosis of the left atrial appendage (LAA). However, the molecular mechanisms underlying this site‐specificity remain poorly understood. Here, we present a comparative single‐cell transcriptional profile of paire...
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| Language: | English |
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Wiley
2023-06-01
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| Series: | Clinical and Translational Medicine |
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| Online Access: | https://doi.org/10.1002/ctm2.1297 |
| _version_ | 1797791888227434496 |
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| author | Jie Yang Hu Tan Mengjia Sun Renzheng Chen Zhao Jian Yuanbin Song Jihang Zhang Shizhu Bian Bo Zhang Yi Zhang Xubin Gao Zhen Chen Boji Wu Xiaowei Ye Hailin Lv Zhen Liu Lan Huang |
| author_facet | Jie Yang Hu Tan Mengjia Sun Renzheng Chen Zhao Jian Yuanbin Song Jihang Zhang Shizhu Bian Bo Zhang Yi Zhang Xubin Gao Zhen Chen Boji Wu Xiaowei Ye Hailin Lv Zhen Liu Lan Huang |
| author_sort | Jie Yang |
| collection | DOAJ |
| description | Abstract Background Atrial fibrillation (AF) is associated with an increased risk of thrombosis of the left atrial appendage (LAA). However, the molecular mechanisms underlying this site‐specificity remain poorly understood. Here, we present a comparative single‐cell transcriptional profile of paired atrial appendages from patients with AF and illustrate the chamber‐specific properties of the main cell types. Methods Single‐cell RNA sequencing analysis of matched atrial appendage samples from three patients with persistent AF was evaluated by 10× genomics. The AF mice model was created using Tbx5 knockout mice. Validation experiments were performed by glutathione S‐transferase pull‐down assays, coimmunoprecipitation (Co‐IP), cleavage assays and shear stress experiments in vitro. Results In LAA, phenotype switching from endothelial cells to fibroblasts and inflammation associated with proinflammatory macrophage infiltration were observed. Importantly, the coagulation cascade is highly enriched in LAA endocardial endothelial cells (EECs), accompanying the up‐regulation of a disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS1) and the down‐regulation of the tissue factor pathway inhibitor (TFPI) and TFPI2. Similar alterations were verified in an AF mouse model (Tbx5+/−) and EECs treated with simulated AF shear stress in vitro. Furthermore, we revealed that the cleavage of both TFPI and TFPI2 based on their interaction with ADAMTS1 would lead to loss of anticoagulant activities of EECs. Conclusions This study highlights the decrease in the anticoagulant status of EECs in LAA as a potential mechanism underlying the propensity for thrombosis, which may aid the development of anticoagulation therapeutic approaches targeting functionally distinct cell subsets or molecules during AF. |
| first_indexed | 2024-03-13T02:25:14Z |
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| institution | Directory Open Access Journal |
| issn | 2001-1326 |
| language | English |
| last_indexed | 2024-03-13T02:25:14Z |
| publishDate | 2023-06-01 |
| publisher | Wiley |
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| series | Clinical and Translational Medicine |
| spelling | doaj.art-886312f4883741bea507372d9e79f9f52023-06-30T05:10:38ZengWileyClinical and Translational Medicine2001-13262023-06-01136n/an/a10.1002/ctm2.1297Single‐cell RNA sequencing reveals a mechanism underlying the susceptibility of the left atrial appendage to intracardiac thrombogenesis during atrial fibrillationJie Yang0Hu Tan1Mengjia Sun2Renzheng Chen3Zhao Jian4Yuanbin Song5Jihang Zhang6Shizhu Bian7Bo Zhang8Yi Zhang9Xubin Gao10Zhen Chen11Boji Wu12Xiaowei Ye13Hailin Lv14Zhen Liu15Lan Huang16Institute of Cardiovascular Diseases of PLA the Second Affiliated Hospital Army Medical University (Third Military Medical University) Chongqing ChinaInstitute of Cardiovascular Diseases of PLA the Second Affiliated Hospital Army Medical University (Third Military Medical University) Chongqing ChinaInstitute of Cardiovascular Diseases of PLA the Second Affiliated Hospital Army Medical University (Third Military Medical University) Chongqing ChinaInstitute of Cardiovascular Diseases of PLA the Second Affiliated Hospital Army Medical University (Third Military Medical University) Chongqing ChinaDepartment of Cardiovascular Surgery the Second Affiliated Hospital Army Medical University (Third Military Medical University) Chongqing ChinaInstitute of Cardiovascular Diseases of PLA the Second Affiliated Hospital Army Medical University (Third Military Medical University) Chongqing ChinaInstitute of Cardiovascular Diseases of PLA the Second Affiliated Hospital Army Medical University (Third Military Medical University) Chongqing ChinaInstitute of Cardiovascular Diseases of PLA the Second Affiliated Hospital Army Medical University (Third Military Medical University) Chongqing ChinaInstitute of Cardiovascular Diseases of PLA the Second Affiliated Hospital Army Medical University (Third Military Medical University) Chongqing ChinaInstitute of Cardiovascular Diseases of PLA the Second Affiliated Hospital Army Medical University (Third Military Medical University) Chongqing ChinaInstitute of Cardiovascular Diseases of PLA the Second Affiliated Hospital Army Medical University (Third Military Medical University) Chongqing ChinaInstitute of Cardiovascular Diseases of PLA the Second Affiliated Hospital Army Medical University (Third Military Medical University) Chongqing ChinaInstitute of Cardiovascular Diseases of PLA the Second Affiliated Hospital Army Medical University (Third Military Medical University) Chongqing ChinaInstitute of Cardiovascular Diseases of PLA the Second Affiliated Hospital Army Medical University (Third Military Medical University) Chongqing ChinaInstitute of Cardiovascular Diseases of PLA the Second Affiliated Hospital Army Medical University (Third Military Medical University) Chongqing ChinaInstitute of Cardiovascular Diseases of PLA the Second Affiliated Hospital Army Medical University (Third Military Medical University) Chongqing ChinaInstitute of Cardiovascular Diseases of PLA the Second Affiliated Hospital Army Medical University (Third Military Medical University) Chongqing ChinaAbstract Background Atrial fibrillation (AF) is associated with an increased risk of thrombosis of the left atrial appendage (LAA). However, the molecular mechanisms underlying this site‐specificity remain poorly understood. Here, we present a comparative single‐cell transcriptional profile of paired atrial appendages from patients with AF and illustrate the chamber‐specific properties of the main cell types. Methods Single‐cell RNA sequencing analysis of matched atrial appendage samples from three patients with persistent AF was evaluated by 10× genomics. The AF mice model was created using Tbx5 knockout mice. Validation experiments were performed by glutathione S‐transferase pull‐down assays, coimmunoprecipitation (Co‐IP), cleavage assays and shear stress experiments in vitro. Results In LAA, phenotype switching from endothelial cells to fibroblasts and inflammation associated with proinflammatory macrophage infiltration were observed. Importantly, the coagulation cascade is highly enriched in LAA endocardial endothelial cells (EECs), accompanying the up‐regulation of a disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS1) and the down‐regulation of the tissue factor pathway inhibitor (TFPI) and TFPI2. Similar alterations were verified in an AF mouse model (Tbx5+/−) and EECs treated with simulated AF shear stress in vitro. Furthermore, we revealed that the cleavage of both TFPI and TFPI2 based on their interaction with ADAMTS1 would lead to loss of anticoagulant activities of EECs. Conclusions This study highlights the decrease in the anticoagulant status of EECs in LAA as a potential mechanism underlying the propensity for thrombosis, which may aid the development of anticoagulation therapeutic approaches targeting functionally distinct cell subsets or molecules during AF.https://doi.org/10.1002/ctm2.1297ADAMTS1atrial fibrillationendocardial endothelial cellssingle‐cell RNA‐sequencingTFPI familythrombogenesis |
| spellingShingle | Jie Yang Hu Tan Mengjia Sun Renzheng Chen Zhao Jian Yuanbin Song Jihang Zhang Shizhu Bian Bo Zhang Yi Zhang Xubin Gao Zhen Chen Boji Wu Xiaowei Ye Hailin Lv Zhen Liu Lan Huang Single‐cell RNA sequencing reveals a mechanism underlying the susceptibility of the left atrial appendage to intracardiac thrombogenesis during atrial fibrillation Clinical and Translational Medicine ADAMTS1 atrial fibrillation endocardial endothelial cells single‐cell RNA‐sequencing TFPI family thrombogenesis |
| title | Single‐cell RNA sequencing reveals a mechanism underlying the susceptibility of the left atrial appendage to intracardiac thrombogenesis during atrial fibrillation |
| title_full | Single‐cell RNA sequencing reveals a mechanism underlying the susceptibility of the left atrial appendage to intracardiac thrombogenesis during atrial fibrillation |
| title_fullStr | Single‐cell RNA sequencing reveals a mechanism underlying the susceptibility of the left atrial appendage to intracardiac thrombogenesis during atrial fibrillation |
| title_full_unstemmed | Single‐cell RNA sequencing reveals a mechanism underlying the susceptibility of the left atrial appendage to intracardiac thrombogenesis during atrial fibrillation |
| title_short | Single‐cell RNA sequencing reveals a mechanism underlying the susceptibility of the left atrial appendage to intracardiac thrombogenesis during atrial fibrillation |
| title_sort | single cell rna sequencing reveals a mechanism underlying the susceptibility of the left atrial appendage to intracardiac thrombogenesis during atrial fibrillation |
| topic | ADAMTS1 atrial fibrillation endocardial endothelial cells single‐cell RNA‐sequencing TFPI family thrombogenesis |
| url | https://doi.org/10.1002/ctm2.1297 |
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