Your browser doesn't support javascript.
loading
Role of inflammatory signaling pathways involving the CD40-CD40L-TRAF cascade in diabetes and hypertension-insights from animal and human studies.
Strohm, Lea; Daiber, Andreas; Ubbens, Henning; Krishnankutty, Roopesh; Oelze, Matthias; Kuntic, Marin; Hahad, Omar; Klein, Veronique; Hoefer, Imo E; von Kriegsheim, Alex; Kleinert, Hartmut; Atzler, Dorothee; Lurz, Philipp; Weber, Christian; Wild, Philipp S; Münzel, Thomas; Knosalla, Christoph; Lutgens, Esther; Daub, Steffen.
Affiliation
  • Strohm L; Department of Cardiology, Cardiology I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.
  • Daiber A; Department of Cardiology, Cardiology I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany. daiber@uni-mainz.de.
  • Ubbens H; German Center for Cardiovascular Research (DZHK), Partnersite Rhine-Main, Mainz, Germany. daiber@uni-mainz.de.
  • Krishnankutty R; Universitätsmedizin der Johannes Gutenberg-Universität Zentrum für Kardiologie 1, Labor für Molekulare Kardiologie, Geb. 605, Raum 3.262, Langenbeckstr. 1, 55131, Mainz, Germany. daiber@uni-mainz.de.
  • Oelze M; Department of Cardiology, Cardiology I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.
  • Kuntic M; Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
  • Hahad O; Department of Cardiology, Cardiology I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.
  • Klein V; Department of Cardiology, Cardiology I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.
  • Hoefer IE; Department of Cardiology, Cardiology I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.
  • von Kriegsheim A; German Center for Cardiovascular Research (DZHK), Partnersite Rhine-Main, Mainz, Germany.
  • Kleinert H; Department of Cardiology, Cardiology I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.
  • Atzler D; Central Diagnostic Laboratory, UMC Utrecht, Utrecht, The Netherlands.
  • Lurz P; Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
  • Weber C; Department of Pharmacology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.
  • Wild PS; Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians Universität, Munich, Germany.
  • Münzel T; German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany.
  • Knosalla C; Walther Straub Institute of Pharmacology and Toxicology, LMU Munich, Munich, Germany.
  • Lutgens E; Department of Cardiology, Cardiology I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.
  • Daub S; German Center for Cardiovascular Research (DZHK), Partnersite Rhine-Main, Mainz, Germany.
Basic Res Cardiol ; 119(4): 1-18, 2024 Aug.
Article in En | MEDLINE | ID: mdl-38554187
ABSTRACT
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.
Subject(s)
Key words

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Signal Transduction / CD40 Antigens / CD40 Ligand / Hypertension Limits: Aged / Animals / Female / Humans / Male / Middle aged Language: En Journal: Basic Res Cardiol Year: 2024 Document type: Article Affiliation country: Germany

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Signal Transduction / CD40 Antigens / CD40 Ligand / Hypertension Limits: Aged / Animals / Female / Humans / Male / Middle aged Language: En Journal: Basic Res Cardiol Year: 2024 Document type: Article Affiliation country: Germany