دورية أكاديمية
Macrophage-Expressed Coagulation Factor VII Promotes Adverse Cardiac Remodeling.
| العنوان: | Macrophage-Expressed Coagulation Factor VII Promotes Adverse Cardiac Remodeling. |
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| المؤلفون: | Garlapati V; Center for Thrombosis and Hemostasis (V.G., Q.L., J.P., M.A., T.S.N., K.G., M.M., S.F., W.R., P.W.), University Medical Center Mainz, Germany.; Department of Cardiology (V.G., Q.L., M.A., M.M., S.F., P.W.), University Medical Center Mainz, Germany.; German Center for Cardiovascular Research-Partner site Rhine-Main (V.G., Q.L., M.A., M.M., W.R., P.W.), University Medical Center Mainz, Germany., Luo Q; Center for Thrombosis and Hemostasis (V.G., Q.L., J.P., M.A., T.S.N., K.G., M.M., S.F., W.R., P.W.), University Medical Center Mainz, Germany.; Department of Cardiology (V.G., Q.L., M.A., M.M., S.F., P.W.), University Medical Center Mainz, Germany.; German Center for Cardiovascular Research-Partner site Rhine-Main (V.G., Q.L., M.A., M.M., W.R., P.W.), University Medical Center Mainz, Germany.; Department of Biochemistry, Cardiovascular Research Maastricht University, the Netherlands (Q.L.)., Posma J; Center for Thrombosis and Hemostasis (V.G., Q.L., J.P., M.A., T.S.N., K.G., M.M., S.F., W.R., P.W.), University Medical Center Mainz, Germany., Aluia M; Center for Thrombosis and Hemostasis (V.G., Q.L., J.P., M.A., T.S.N., K.G., M.M., S.F., W.R., P.W.), University Medical Center Mainz, Germany.; Department of Cardiology (V.G., Q.L., M.A., M.M., S.F., P.W.), University Medical Center Mainz, Germany.; German Center for Cardiovascular Research-Partner site Rhine-Main (V.G., Q.L., M.A., M.M., W.R., P.W.), University Medical Center Mainz, Germany., Nguyen TS; Center for Thrombosis and Hemostasis (V.G., Q.L., J.P., M.A., T.S.N., K.G., M.M., S.F., W.R., P.W.), University Medical Center Mainz, Germany., Grunz K; Center for Thrombosis and Hemostasis (V.G., Q.L., J.P., M.A., T.S.N., K.G., M.M., S.F., W.R., P.W.), University Medical Center Mainz, Germany., Molitor M; Center for Thrombosis and Hemostasis (V.G., Q.L., J.P., M.A., T.S.N., K.G., M.M., S.F., W.R., P.W.), University Medical Center Mainz, Germany.; Department of Cardiology (V.G., Q.L., M.A., M.M., S.F., P.W.), University Medical Center Mainz, Germany.; German Center for Cardiovascular Research-Partner site Rhine-Main (V.G., Q.L., M.A., M.M., W.R., P.W.), University Medical Center Mainz, Germany., Finger S; Center for Thrombosis and Hemostasis (V.G., Q.L., J.P., M.A., T.S.N., K.G., M.M., S.F., W.R., P.W.), University Medical Center Mainz, Germany.; Department of Cardiology (V.G., Q.L., M.A., M.M., S.F., P.W.), University Medical Center Mainz, Germany., Harms G; Institute of Immunology and Research Center for Immunotherapy (G.H., T.B.), University Medical Center Mainz, Germany.; Cell Biology Unit (G.H.), University Medical Center Mainz, Germany.; Department of Biology, Wilkes University, Wilkes-Barre, PA (G.H.)., Bopp T; Institute of Immunology and Research Center for Immunotherapy (G.H., T.B.), University Medical Center Mainz, Germany., Ruf W; Center for Thrombosis and Hemostasis (V.G., Q.L., J.P., M.A., T.S.N., K.G., M.M., S.F., W.R., P.W.), University Medical Center Mainz, Germany.; German Center for Cardiovascular Research-Partner site Rhine-Main (V.G., Q.L., M.A., M.M., W.R., P.W.), University Medical Center Mainz, Germany.; Department of Immunology and Microbiology, Scripps Research, La Jolla, CA (W.R.)., Wenzel P; Center for Thrombosis and Hemostasis (V.G., Q.L., J.P., M.A., T.S.N., K.G., M.M., S.F., W.R., P.W.), University Medical Center Mainz, Germany.; Department of Cardiology (V.G., Q.L., M.A., M.M., S.F., P.W.), University Medical Center Mainz, Germany.; German Center for Cardiovascular Research-Partner site Rhine-Main (V.G., Q.L., M.A., M.M., W.R., P.W.), University Medical Center Mainz, Germany. |
| المصدر: | Circulation research [Circ Res] 2024 Sep 27; Vol. 135 (8), pp. 841-855. Date of Electronic Publication: 2024 Sep 05. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Lippincott Williams & Wilkins Country of Publication: United States NLM ID: 0047103 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1524-4571 (Electronic) Linking ISSN: 00097330 NLM ISO Abbreviation: Circ Res Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Baltimore, MD : Lippincott Williams & Wilkins Original Publication: Baltimore, Md. Grune & Stratton. |
| مواضيع طبية MeSH: | Macrophages*/metabolism , Ventricular Remodeling* , Myocardial Infarction*/metabolism , Myocardial Infarction*/pathology , Myocardial Infarction*/genetics , Receptor, PAR-2*/metabolism , Receptor, PAR-2*/genetics , Receptor, PAR-2*/deficiency , Mice, Inbred C57BL*, Animals ; Mice ; Factor VIIa/metabolism ; Male ; Signal Transduction ; Mice, Knockout ; Transforming Growth Factor beta1/metabolism ; Integrin beta1/metabolism ; Integrin beta1/genetics ; Thromboplastin/metabolism ; Thromboplastin/genetics ; Fibrosis |
| مستخلص: | 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 PAR2 R38E 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 fl/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 PAR2 R38E 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. Competing Interests: W. Ruf is a consultant and received research support from Endpoint Health. W. Ruf and P. Wenzel have filed a patent application on the use of inhibitors of the tissue factor (TF)-PAR2 (protease activated receptor 2) signaling for the treatment or prevention of heart failure (PCT/EP2021/082355). The other authors report no conflicts. |
| فهرسة مساهمة: | Keywords: coagulation factors; fibrosis; heart failure; inflammation; macrophages; myocardial infarction |
| المشرفين على المادة: | 0 (Receptor, PAR-2) EC 3.4.21.21 (Factor VIIa) 0 (Transforming Growth Factor beta1) 0 (Integrin beta1) 9035-58-9 (Thromboplastin) |
| تواريخ الأحداث: | Date Created: 20240905 Date Completed: 20240926 Latest Revision: 20240926 |
| رمز التحديث: | 20240927 |
| DOI: | 10.1161/CIRCRESAHA.123.324114 |
| PMID: | 39234697 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1524-4571 |
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| DOI: | 10.1161/CIRCRESAHA.123.324114 |