巨噬细胞表达的凝血因子 7 促进不良心脏重塑

IF 16.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Circulation research Pub Date : 2024-09-27 Epub Date: 2024-09-05 DOI:10.1161/CIRCRESAHA.123.324114
Venkata Garlapati, Qi Luo, Jens Posma, Melania Aluia, Than Son Nguyen, Kristin Grunz, Michael Molitor, Stefanie Finger, Gregory Harms, Tobias Bopp, Wolfram Ruf, Philip Wenzel
{"title":"巨噬细胞表达的凝血因子 7 促进不良心脏重塑","authors":"Venkata Garlapati, Qi Luo, Jens Posma, Melania Aluia, Than Son Nguyen, Kristin Grunz, Michael Molitor, Stefanie Finger, Gregory Harms, Tobias Bopp, Wolfram Ruf, Philip Wenzel","doi":"10.1161/CIRCRESAHA.123.324114","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Excess fibrotic remodeling causes cardiac dysfunction in ischemic heart disease, driven by MAP (mitogen-activated protein) kinase-dependent TGF-ß1 (transforming growth factor-ß1) activation by coagulation signaling of myeloid cells. How coagulation-inflammatory circuits can be specifically targeted to achieve beneficial macrophage reprogramming after myocardial infarction (MI) is not completely understood.</p><p><strong>Methods: </strong>Mice with permanent ligation of the left anterior descending artery were used to model nonreperfused MI and analyzed by single-cell RNA sequencing, protein expression changes, confocal microscopy, and longitudinal monitoring of recovery. We probed the role of the tissue factor (TF)-FVIIa (activated factor VII)-integrin ß1-PAR2 (protease-activated receptor 2) signaling complex by utilizing genetic mouse models and pharmacological intervention.</p><p><strong>Results: </strong>Cleavage-insensitive PAR2<sup>R38E</sup> and myeloid cell integrin ß1-deficient mice had improved cardiac function after MI compared with controls. Proximity ligation assays of monocytic cells demonstrated that colocalization of FVIIa with integrin ß1 was diminished in monocyte/macrophage FVII-deficient mice after MI. Compared with controls, F7<sup>fl/fl</sup> CX3CR1 (CX3C motif chemokine receptor 1)<sup>Cre</sup> mice showed reduced TGF-ß1 and MAP kinase activation, as well as cardiac dysfunction after MI, despite unaltered overall recruitment of myeloid cells. Single-cell mRNA sequencing of CD45 (cluster of differentiation 45)<sup>+</sup> cells 3 and 7 days after MI uncovered a trajectory from recruited monocytes to inflammatory TF<sup>+</sup>/TREM (triggered receptor expressed on myeloid cells) 1<sup>+</sup> macrophages requiring F7. As early as 7 days after MI, macrophage F7 deletion led to an expansion of reparative Olfml 3 (olfactomedin-like protein 3)<sup>+</sup> macrophages and, conversely, to a reduction of TF<sup>+</sup>/TREM1<sup>+</sup> macrophages, which were also reduced in PAR2<sup>R38E</sup> mice. Short-term treatment from days 1 to 5 after nonreperfused MI with a monoclonal antibody inhibiting the macrophage TF-FVIIa-PAR2 signaling complex without anticoagulant activity improved cardiac dysfunction, decreased excess fibrosis, attenuated vascular endothelial dysfunction, and increased survival 28 days after MI.</p><p><strong>Conclusions: </strong>Extravascular TF-FVIIa-PAR2 complex signaling drives inflammatory macrophage polarization in ischemic heart disease. Targeting this signaling complex for specific therapeutic macrophage reprogramming following MI attenuates cardiac fibrosis and improves cardiovascular function.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":null,"pages":null},"PeriodicalIF":16.5000,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Macrophage-Expressed Coagulation Factor VII Promotes Adverse Cardiac Remodeling.\",\"authors\":\"Venkata Garlapati, Qi Luo, Jens Posma, Melania Aluia, Than Son Nguyen, Kristin Grunz, Michael Molitor, Stefanie Finger, Gregory Harms, Tobias Bopp, Wolfram Ruf, Philip Wenzel\",\"doi\":\"10.1161/CIRCRESAHA.123.324114\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Excess fibrotic remodeling causes cardiac dysfunction in ischemic heart disease, driven by MAP (mitogen-activated protein) kinase-dependent TGF-ß1 (transforming growth factor-ß1) activation by coagulation signaling of myeloid cells. How coagulation-inflammatory circuits can be specifically targeted to achieve beneficial macrophage reprogramming after myocardial infarction (MI) is not completely understood.</p><p><strong>Methods: </strong>Mice with permanent ligation of the left anterior descending artery were used to model nonreperfused MI and analyzed by single-cell RNA sequencing, protein expression changes, confocal microscopy, and longitudinal monitoring of recovery. We probed the role of the tissue factor (TF)-FVIIa (activated factor VII)-integrin ß1-PAR2 (protease-activated receptor 2) signaling complex by utilizing genetic mouse models and pharmacological intervention.</p><p><strong>Results: </strong>Cleavage-insensitive PAR2<sup>R38E</sup> and myeloid cell integrin ß1-deficient mice had improved cardiac function after MI compared with controls. Proximity ligation assays of monocytic cells demonstrated that colocalization of FVIIa with integrin ß1 was diminished in monocyte/macrophage FVII-deficient mice after MI. Compared with controls, F7<sup>fl/fl</sup> CX3CR1 (CX3C motif chemokine receptor 1)<sup>Cre</sup> mice showed reduced TGF-ß1 and MAP kinase activation, as well as cardiac dysfunction after MI, despite unaltered overall recruitment of myeloid cells. Single-cell mRNA sequencing of CD45 (cluster of differentiation 45)<sup>+</sup> cells 3 and 7 days after MI uncovered a trajectory from recruited monocytes to inflammatory TF<sup>+</sup>/TREM (triggered receptor expressed on myeloid cells) 1<sup>+</sup> macrophages requiring F7. As early as 7 days after MI, macrophage F7 deletion led to an expansion of reparative Olfml 3 (olfactomedin-like protein 3)<sup>+</sup> macrophages and, conversely, to a reduction of TF<sup>+</sup>/TREM1<sup>+</sup> macrophages, which were also reduced in PAR2<sup>R38E</sup> mice. Short-term treatment from days 1 to 5 after nonreperfused MI with a monoclonal antibody inhibiting the macrophage TF-FVIIa-PAR2 signaling complex without anticoagulant activity improved cardiac dysfunction, decreased excess fibrosis, attenuated vascular endothelial dysfunction, and increased survival 28 days after MI.</p><p><strong>Conclusions: </strong>Extravascular TF-FVIIa-PAR2 complex signaling drives inflammatory macrophage polarization in ischemic heart disease. Targeting this signaling complex for specific therapeutic macrophage reprogramming following MI attenuates cardiac fibrosis and improves cardiovascular function.</p>\",\"PeriodicalId\":10147,\"journal\":{\"name\":\"Circulation research\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":16.5000,\"publicationDate\":\"2024-09-27\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Circulation research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1161/CIRCRESAHA.123.324114\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/9/5 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"CARDIAC & CARDIOVASCULAR SYSTEMS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Circulation research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1161/CIRCRESAHA.123.324114","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/9/5 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
引用次数: 0

摘要

背景:在缺血性心脏病中,过多的纤维重塑会导致心脏功能障碍,其驱动因素是骨髓细胞凝血信号的MAP(丝裂原活化蛋白)激酶依赖性TGF-ß1(转化生长因子-ß1)激活。心肌梗死(MI)后如何有针对性地针对凝血-炎症回路进行有益的巨噬细胞重编程,目前还不完全清楚:方法:用永久性结扎左前降支动脉的小鼠建立非再灌注心肌梗死模型,并通过单细胞RNA测序、蛋白质表达变化、共聚焦显微镜和纵向恢复监测进行分析。我们利用遗传小鼠模型和药物干预,探究了组织因子(TF)-因子7(F7)-整合素ß1-PAR2(蛋白酶激活受体2)信号复合体的作用:结果:与对照组相比,对裂解不敏感的PAR2R38E和骨髓细胞整合素ß1缺陷小鼠在心肌梗死后的心脏功能有所改善。单核细胞的邻近接合试验表明,缺失单核细胞/巨噬细胞 F7 的小鼠在心肌梗死后 F7 与整合素 ß1 的共定位减少。与对照组相比,F7fl/fl CX3CR1Cre小鼠的TGF-ß1和MAP激酶活化以及心肌梗死后的心脏功能障碍均有所降低,尽管髓系细胞的整体招募没有改变。心肌梗死后3天和7天,CD45(分化簇45)+细胞的单细胞mRNA测序发现了从招募的单核细胞到炎性TF+/F7+/TREM(髓样细胞上表达的触发受体)1+巨噬细胞的轨迹。早在心肌梗死后 7 天,巨噬细胞 F7 缺失就导致了修复性 Olfml(嗅探素)3+ 巨噬细胞的扩增,反之,TF+/F7+/TREM1+ 巨噬细胞的减少,PAR2R38E 小鼠的巨噬细胞也减少了。在非再灌注心肌梗死后的第1至5天,使用一种抑制巨噬细胞TF-F7-PAR2信号复合物的单克隆抗体进行短期治疗,但不具有抗凝活性,这种抗体可改善心功能障碍,减少过度纤维化,减轻血管内皮功能障碍,并提高心肌梗死后28天的存活率:结论:血管外 TF-F7-PAR2 复合物信号驱动缺血性心脏病中巨噬细胞的炎症极化。结论:血管外 TF-F7-PAR2 复合物信号驱动缺血性心脏病中的炎性巨噬细胞极化,针对这一信号复合物进行特定的治疗性巨噬细胞重编程可减轻心肌梗死后的心脏纤维化并改善心血管功能。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
Macrophage-Expressed Coagulation Factor VII Promotes Adverse Cardiac Remodeling.

Background: Excess fibrotic remodeling causes cardiac dysfunction in ischemic heart disease, driven by MAP (mitogen-activated protein) kinase-dependent TGF-ß1 (transforming growth factor-ß1) activation by coagulation signaling of myeloid cells. How coagulation-inflammatory circuits can be specifically targeted to achieve beneficial macrophage reprogramming after myocardial infarction (MI) is not completely understood.

Methods: Mice with permanent ligation of the left anterior descending artery were used to model nonreperfused MI and analyzed by single-cell RNA sequencing, protein expression changes, confocal microscopy, and longitudinal monitoring of recovery. We probed the role of the tissue factor (TF)-FVIIa (activated factor VII)-integrin ß1-PAR2 (protease-activated receptor 2) signaling complex by utilizing genetic mouse models and pharmacological intervention.

Results: Cleavage-insensitive PAR2R38E and myeloid cell integrin ß1-deficient mice had improved cardiac function after MI compared with controls. Proximity ligation assays of monocytic cells demonstrated that colocalization of FVIIa with integrin ß1 was diminished in monocyte/macrophage FVII-deficient mice after MI. Compared with controls, F7fl/fl CX3CR1 (CX3C motif chemokine receptor 1)Cre mice showed reduced TGF-ß1 and MAP kinase activation, as well as cardiac dysfunction after MI, despite unaltered overall recruitment of myeloid cells. Single-cell mRNA sequencing of CD45 (cluster of differentiation 45)+ cells 3 and 7 days after MI uncovered a trajectory from recruited monocytes to inflammatory TF+/TREM (triggered receptor expressed on myeloid cells) 1+ macrophages requiring F7. As early as 7 days after MI, macrophage F7 deletion led to an expansion of reparative Olfml 3 (olfactomedin-like protein 3)+ macrophages and, conversely, to a reduction of TF+/TREM1+ macrophages, which were also reduced in PAR2R38E mice. Short-term treatment from days 1 to 5 after nonreperfused MI with a monoclonal antibody inhibiting the macrophage TF-FVIIa-PAR2 signaling complex without anticoagulant activity improved cardiac dysfunction, decreased excess fibrosis, attenuated vascular endothelial dysfunction, and increased survival 28 days after MI.

Conclusions: Extravascular TF-FVIIa-PAR2 complex signaling drives inflammatory macrophage polarization in ischemic heart disease. Targeting this signaling complex for specific therapeutic macrophage reprogramming following MI attenuates cardiac fibrosis and improves cardiovascular function.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Circulation research
Circulation research 医学-外周血管病
CiteScore
29.60
自引率
2.00%
发文量
535
审稿时长
3-6 weeks
期刊介绍: Circulation Research is a peer-reviewed journal that serves as a forum for the highest quality research in basic cardiovascular biology. The journal publishes studies that utilize state-of-the-art approaches to investigate mechanisms of human disease, as well as translational and clinical research that provide fundamental insights into the basis of disease and the mechanism of therapies. Circulation Research has a broad audience that includes clinical and academic cardiologists, basic cardiovascular scientists, physiologists, cellular and molecular biologists, and cardiovascular pharmacologists. The journal aims to advance the understanding of cardiovascular biology and disease by disseminating cutting-edge research to these diverse communities. In terms of indexing, Circulation Research is included in several prominent scientific databases, including BIOSIS, CAB Abstracts, Chemical Abstracts, Current Contents, EMBASE, and MEDLINE. This ensures that the journal's articles are easily discoverable and accessible to researchers in the field. Overall, Circulation Research is a reputable publication that attracts high-quality research and provides a platform for the dissemination of important findings in basic cardiovascular biology and its translational and clinical applications.
期刊最新文献
Pneumonia Induced Rise in Glucagon Promotes Endothelial Damage and Thrombogenicity. LRP1 Repression by SNAIL Results in ECM Remodeling in Genetic Risk for Vascular Diseases. Kindlin-2 Phase Separation in Response to Flow Controls Vascular Stability. CAR-Macrophage Therapy Alleviates Myocardial Ischemia-Reperfusion Injury. Transformation of the Kidney into a Pathological Neuro-Immune-Endocrine Organ.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1