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Role of inflammatory signaling pathways involving the CD40–CD40L–TRAF cascade in diabetes and hypertension—insights from animal and human studies

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Názov: Role of inflammatory signaling pathways involving the CD40–CD40L–TRAF cascade in diabetes and hypertension—insights from animal and human studies
Autori: Lea Strohm, Andreas Daiber, Henning Ubbens, Roopesh Krishnankutty, Matthias Oelze, Marin Kuntic, Omar Hahad, Veronique Klein, Imo E. Hoefer, Alex von Kriegsheim, Hartmut Kleinert, Dorothee Atzler, Philipp Lurz, Christian Weber, Philipp S. Wild, Thomas Münzel, Christoph Knosalla, Esther Lutgens, Steffen Daub
Prispievatelia: Johannes Gutenberg-Universität Mainz, Centraal Diagnostisch Laboratorium, UMC Utrecht Holding, Circulatory Health
Zdroj: Basic Res Cardiol
Informácie o vydavateľovi: Springer Science and Business Media LLC, 2024.
Rok vydania: 2024
Predmety: Male, Physiology, CD40 Ligand, 610 Medizin, Coronary Disease, Comorbidities, Mice, Physiology (medical), 610 Medical sciences, Humans, Animals, CD40L–CD40–TRAF6 axis, Mice, Inbred C57BL [MeSH], Aged [MeSH], Original Contribution, Coronary Disease/metabolism [MeSH], CD40 Ligand/metabolism [MeSH], Hypertension/immunology [MeSH], Male [MeSH], Inflammation/immunology [MeSH], Female [MeSH], Hypertension/metabolism [MeSH], Humans [MeSH], Inflammation, TNF Receptor-Associated Factor 6/metabolism [MeSH], Coronary Disease/immunology [MeSH], Middle Aged [MeSH], Animals [MeSH], CD40 Antigens/metabolism [MeSH], Oxidative stress, Diabetes, Mice [MeSH], Coronary heart disease, Inflammation/metabolism [MeSH], Signal Transduction [MeSH], Hypertension, CD40 Antigens, Aged, TNF Receptor-Associated Factor 6, Middle Aged, 3. Good health, Mice, Inbred C57BL, Female, Cardiology and Cardiovascular Medicine, Signal Transduction
Popis: CD40L–CD40–TRAF signaling plays a role in atherosclerosis progression and affects the pathogenesis of coronary heart disease (CHD). We tested the hypothesis that CD40L–CD40–TRAF signaling is a potential therapeutic target in hyperlipidemia, diabetes, and hypertension. In mouse models of hyperlipidemia plus diabetes (db/db mice) or hypertension (1 mg/kg/d angiotensin-II for 7 days), TRAF6 inhibitor treatment (2.5 mg/kg/d for 7 or 14 days) normalized markers of oxidative stress and inflammation. As diabetes and hypertension are important comorbidities aggravating CHD, we explored whether the CD40L–CD40–TRAF signaling cascade and their associated inflammatory pathways are expressed in CHD patients suffering from comorbidities. Therefore, we analyzed vascular bypass material (aorta or internal mammary artery) and plasma from patients with CHD with diabetes and/or hypertension. Our Olink targeted plasma proteomic analysis using the IMMUNO-ONCOLOGY panel revealed a pattern of step-wise increase for 13/92 markers of low-grade inflammation with significant changes. CD40L or CD40 significantly correlated with 38 or 56 other inflammatory targets. In addition, specific gene clusters that correlate with the comorbidities were identified in isolated aortic mRNA of CHD patients through RNA-sequencing. These signaling clusters comprised CD40L–CD40–TRAF, immune system, hemostasis, muscle contraction, metabolism of lipids, developmental biology, and apoptosis. Finally, immunological analysis revealed key markers correlated with comorbidities in CHD patients, such as CD40L, NOX2, CD68, and 3-nitrotyrosine. These data indicate that comorbidities increase inflammatory pathways in CHD, and targeting these pathways will be beneficial in reducing cardiovascular events in CHD patients with comorbidities.
Druh dokumentu: Article
Other literature type
Popis súboru: application/pdf
Jazyk: English
ISSN: 1435-1803
DOI: 10.1007/s00395-024-01045-1
DOI: 10.25358/openscience-11534
Prístupová URL adresa: https://pubmed.ncbi.nlm.nih.gov/38554187
https://openscience.ub.uni-mainz.de/handle/20.500.12030/11555
https://doi.org/10.25358/openscience-11534
https://dspace.library.uu.nl/handle/1874/455633
https://repository.publisso.de/resource/frl:6512252
https://epub.ub.uni-muenchen.de/117666/
Rights: CC BY
Prístupové číslo: edsair.doi.dedup.....c0cb0a44549113e76782185c65538f30
Databáza: OpenAIRE
Popis
Abstrakt:CD40L–CD40–TRAF signaling plays a role in atherosclerosis progression and affects the pathogenesis of coronary heart disease (CHD). We tested the hypothesis that CD40L–CD40–TRAF signaling is a potential therapeutic target in hyperlipidemia, diabetes, and hypertension. In mouse models of hyperlipidemia plus diabetes (db/db mice) or hypertension (1 mg/kg/d angiotensin-II for 7 days), TRAF6 inhibitor treatment (2.5 mg/kg/d for 7 or 14 days) normalized markers of oxidative stress and inflammation. As diabetes and hypertension are important comorbidities aggravating CHD, we explored whether the CD40L–CD40–TRAF signaling cascade and their associated inflammatory pathways are expressed in CHD patients suffering from comorbidities. Therefore, we analyzed vascular bypass material (aorta or internal mammary artery) and plasma from patients with CHD with diabetes and/or hypertension. Our Olink targeted plasma proteomic analysis using the IMMUNO-ONCOLOGY panel revealed a pattern of step-wise increase for 13/92 markers of low-grade inflammation with significant changes. CD40L or CD40 significantly correlated with 38 or 56 other inflammatory targets. In addition, specific gene clusters that correlate with the comorbidities were identified in isolated aortic mRNA of CHD patients through RNA-sequencing. These signaling clusters comprised CD40L–CD40–TRAF, immune system, hemostasis, muscle contraction, metabolism of lipids, developmental biology, and apoptosis. Finally, immunological analysis revealed key markers correlated with comorbidities in CHD patients, such as CD40L, NOX2, CD68, and 3-nitrotyrosine. These data indicate that comorbidities increase inflammatory pathways in CHD, and targeting these pathways will be beneficial in reducing cardiovascular events in CHD patients with comorbidities.
ISSN:14351803
DOI:10.1007/s00395-024-01045-1