CD40-TRAF6 inhibition suppresses cardiovascular inflammation, oxidative stress and functional complications in a mouse model of arterial hypertension
Cardiovascular disease is the leading cause of disease burden and death worldwide and is fueled by vascular inflammation. CD40L–CD40–TRAF signaling is involved in the progression of atherosclerosis and drives the development of coronary heart disease (CHD). The present study investigates whether the...
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Elsevier
2025-03-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231725000333 |
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| author | Lea Strohm Henning Ubbens Dominika Mihalikova Alexander Czarnowski Paul Stamm Michael Molitor Stefanie Finger Matthias Oelze Dorothee Atzler Philip Wenzel Philipp Lurz Thomas Münzel Christian Weber Esther Lutgens Andreas Daiber Steffen Daub |
| author_facet | Lea Strohm Henning Ubbens Dominika Mihalikova Alexander Czarnowski Paul Stamm Michael Molitor Stefanie Finger Matthias Oelze Dorothee Atzler Philip Wenzel Philipp Lurz Thomas Münzel Christian Weber Esther Lutgens Andreas Daiber Steffen Daub |
| author_sort | Lea Strohm |
| collection | DOAJ |
| description | Cardiovascular disease is the leading cause of disease burden and death worldwide and is fueled by vascular inflammation. CD40L–CD40–TRAF signaling is involved in the progression of atherosclerosis and drives the development of coronary heart disease (CHD). The present study investigates whether the CD40L-CD40-TRAF6 signaling pathway with focus on immune cells and adipocytes could be a therapeutic target in arterial hypertension.Arterial hypertension was induced in WT (C57BL6/J) and cell-specific CD40(L) knockout mice (AdipoqCre x CD40 fl/fl, CD4Cre x CD40 fl/fl, CD19Cre x CD40 fl/fl, and GP1baCre x CD40L fl/fl) via angiotensin (AT-II) infusion (1 mg/kg/d) for seven days. Hypertensive WT mice were also treated with a CD40-TRAF6 inhibitor (2.5 mg/kg/d, for 7d). The TRAF6 inhibitor treatment normalized endothelial dysfunction and reduced blood pressure in hypertensive wild type animals. Reactive oxygen species production was decreased by TRAF6 inhibition in blood, aorta, heart, kidney, and perivascular fat tissue. Additionally, FACS analysis revealed that TRAF6 inhibition prevents immune cell migration into the aortic vessel wall observed by reduced CD45+ leukocyte, Ly6G+/Ly6C+ neutrophil, and Ly6Chigh inflammatory monocyte content. The hypertensive cell type-specific CD40(L) knockout animals showed only a minor effect on endothelial function, blood pressure, and oxidative stress. Therefore, we conclude that targeting CD40 directly on adipocytes, B-cells, T-cells, or CD40L on platelets is not a promising target to prevent hypertension complications.In summary, TRAF6 inhibition but not adipocyte, B-cell, or T-cell-specific CD40 or platelet-specific CD40L deficiency reduces pathophysiological vascular inflammation in hypertensive mice, suggesting TRAF6 inhibition as a potential therapeutic target in hypertensive patients. |
| format | Article |
| id | doaj-art-960ee9f4044e441e8ed5c7b8a79fed78 |
| institution | Kabale University |
| issn | 2213-2317 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj-art-960ee9f4044e441e8ed5c7b8a79fed782025-02-03T04:16:42ZengElsevierRedox Biology2213-23172025-03-0180103520CD40-TRAF6 inhibition suppresses cardiovascular inflammation, oxidative stress and functional complications in a mouse model of arterial hypertensionLea Strohm0Henning Ubbens1Dominika Mihalikova2Alexander Czarnowski3Paul Stamm4Michael Molitor5Stefanie Finger6Matthias Oelze7Dorothee Atzler8Philip Wenzel9Philipp Lurz10Thomas Münzel11Christian Weber12Esther Lutgens13Andreas Daiber14Steffen Daub15Department of Cardiology, Cardiology I, University Medical Center of the Johannes Gutenberg-University, Mainz, GermanyDepartment of Cardiology, Cardiology I, University Medical Center of the Johannes Gutenberg-University, Mainz, GermanyDepartment of Cardiology, Cardiology I, University Medical Center of the Johannes Gutenberg-University, Mainz, GermanyDepartment of Cardiology, Cardiology I, University Medical Center of the Johannes Gutenberg-University, Mainz, GermanyDepartment of Cardiology, Cardiology I, University Medical Center of the Johannes Gutenberg-University, Mainz, GermanyDepartment of Cardiology, Cardiology I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany; Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany; German Center for Cardiovascular Research (DZHK), Partnersite Rhine-Main, Mainz, GermanyCenter for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University, Mainz, GermanyDepartment of Cardiology, Cardiology I, University Medical Center of the Johannes Gutenberg-University, Mainz, GermanyInstitute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München, Munich, Germany; DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Germany; Walter Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-Universität, Munich, GermanyDepartment of Cardiology, Cardiology I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany; Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany; German Center for Cardiovascular Research (DZHK), Partnersite Rhine-Main, Mainz, GermanyDepartment of Cardiology, Cardiology I, University Medical Center of the Johannes Gutenberg-University, Mainz, GermanyDepartment of Cardiology, Cardiology I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany; Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany; German Center for Cardiovascular Research (DZHK), Partnersite Rhine-Main, Mainz, GermanyInstitute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München, Munich, Germany; DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, GermanyDZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Germany; Mayo Clinic, Dept Cardiovascular Medicine and Immunology, Rochester, MN, USADepartment of Cardiology, Cardiology I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany; Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany; German Center for Cardiovascular Research (DZHK), Partnersite Rhine-Main, Mainz, Germany; Corresponding author. Universitätsmedizin der Johannes Gutenberg-Universität Zentrum für Kardiologie 1 – Labor für Molekulare Kardiologie, Geb. 605 – Raum 3.262, Langenbeckstr. 1, 55131, Mainz, Germany.Department of Cardiology, Cardiology I, University Medical Center of the Johannes Gutenberg-University, Mainz, GermanyCardiovascular disease is the leading cause of disease burden and death worldwide and is fueled by vascular inflammation. CD40L–CD40–TRAF signaling is involved in the progression of atherosclerosis and drives the development of coronary heart disease (CHD). The present study investigates whether the CD40L-CD40-TRAF6 signaling pathway with focus on immune cells and adipocytes could be a therapeutic target in arterial hypertension.Arterial hypertension was induced in WT (C57BL6/J) and cell-specific CD40(L) knockout mice (AdipoqCre x CD40 fl/fl, CD4Cre x CD40 fl/fl, CD19Cre x CD40 fl/fl, and GP1baCre x CD40L fl/fl) via angiotensin (AT-II) infusion (1 mg/kg/d) for seven days. Hypertensive WT mice were also treated with a CD40-TRAF6 inhibitor (2.5 mg/kg/d, for 7d). The TRAF6 inhibitor treatment normalized endothelial dysfunction and reduced blood pressure in hypertensive wild type animals. Reactive oxygen species production was decreased by TRAF6 inhibition in blood, aorta, heart, kidney, and perivascular fat tissue. Additionally, FACS analysis revealed that TRAF6 inhibition prevents immune cell migration into the aortic vessel wall observed by reduced CD45+ leukocyte, Ly6G+/Ly6C+ neutrophil, and Ly6Chigh inflammatory monocyte content. The hypertensive cell type-specific CD40(L) knockout animals showed only a minor effect on endothelial function, blood pressure, and oxidative stress. Therefore, we conclude that targeting CD40 directly on adipocytes, B-cells, T-cells, or CD40L on platelets is not a promising target to prevent hypertension complications.In summary, TRAF6 inhibition but not adipocyte, B-cell, or T-cell-specific CD40 or platelet-specific CD40L deficiency reduces pathophysiological vascular inflammation in hypertensive mice, suggesting TRAF6 inhibition as a potential therapeutic target in hypertensive patients.http://www.sciencedirect.com/science/article/pii/S2213231725000333Arterial hypertensionEndothelial functionBlood pressureInflammationCD40(L)-TRAF6 signaling |
| spellingShingle | Lea Strohm Henning Ubbens Dominika Mihalikova Alexander Czarnowski Paul Stamm Michael Molitor Stefanie Finger Matthias Oelze Dorothee Atzler Philip Wenzel Philipp Lurz Thomas Münzel Christian Weber Esther Lutgens Andreas Daiber Steffen Daub CD40-TRAF6 inhibition suppresses cardiovascular inflammation, oxidative stress and functional complications in a mouse model of arterial hypertension Redox Biology Arterial hypertension Endothelial function Blood pressure Inflammation CD40(L)-TRAF6 signaling |
| title | CD40-TRAF6 inhibition suppresses cardiovascular inflammation, oxidative stress and functional complications in a mouse model of arterial hypertension |
| title_full | CD40-TRAF6 inhibition suppresses cardiovascular inflammation, oxidative stress and functional complications in a mouse model of arterial hypertension |
| title_fullStr | CD40-TRAF6 inhibition suppresses cardiovascular inflammation, oxidative stress and functional complications in a mouse model of arterial hypertension |
| title_full_unstemmed | CD40-TRAF6 inhibition suppresses cardiovascular inflammation, oxidative stress and functional complications in a mouse model of arterial hypertension |
| title_short | CD40-TRAF6 inhibition suppresses cardiovascular inflammation, oxidative stress and functional complications in a mouse model of arterial hypertension |
| title_sort | cd40 traf6 inhibition suppresses cardiovascular inflammation oxidative stress and functional complications in a mouse model of arterial hypertension |
| topic | Arterial hypertension Endothelial function Blood pressure Inflammation CD40(L)-TRAF6 signaling |
| url | http://www.sciencedirect.com/science/article/pii/S2213231725000333 |
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