CD40L controls obesity-associated vascular inflammation, oxidative stress, and endothelial dysfunction in high fat diet-treated and db/db mice.

Abstract

Aims:

CD40 ligand (CD40L) signaling controls vascular oxidative stress and related dysfunction in angiotensin-II-induced arterial hypertension by regulating vascular immune cell recruitment and platelet activation. Here we investigated the role of CD40L in experimental hyperlipidemia.

Methods and results:

Male wild type and CD40L-/- mice (C57BL/6 background) were subjected to high fat diet for sixteen weeks. Weight, cholesterol, HDL, and LDL levels, endothelial function (isometric tension recording), oxidative stress (NADPH oxidase expression, dihydroethidium fluorescence) and inflammatory parameters (inducible nitric oxide synthase, interleukin-6 expression) were assessed. CD40L expression, weight, leptin and lipids were increased, and endothelial dysfunction, oxidative stress and inflammation were more pronounced in wild type mice on a high fat diet, all of which was almost normalized by CD40L deficiency. Similar results were obtained in diabetic db/db mice with CD40/TRAF6 inhibitor (6877002) therapy. In a small human study higher serum sCD40L levels and an inflammatory phenotype were detected in the blood and Aorta ascendens of obese patients (body mass index > 35) that underwent by-pass surgery.

Conclusion:

CD40L controls obesity-associated vascular inflammation, oxidative stress and endothelial dysfunction in mice and potentially humans. Thus, CD40L represents a therapeutic target in lipid metabolic disorders which is a leading cause in cardiovascular disease.

• Authors: Sebastian Steven, Mobin Dib, Michael Hausding, Fatemeh Kashani, Matthias Oelze, Swenja Kröller-Schön, Alina Hanf, Steffen Daub, Siyer Roohani, Yves Gramlich, Esther Lutgens, Eberhard Schulz, Christian Becker, Karl J Lackner, Hartmut Kleinert, Christoph Knosalla, Beate Niesler, Philipp S Wild, Thomas Münzel, Andreas Daiber
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 114 Issue 2 Pg. 312-323 (02 01 2018) ISSN: 1755-3245 [Electronic] England
• PMID: 29036612 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For Permissions, please email: [email protected].

Chemical References

• Anti-Inflammatory Agents
• Antioxidants
• Biomarkers
• Inflammation Mediators
• Interleukin-6
• Lipids
• TNF Receptor-Associated Factor 6
• interleukin-6, mouse
• CD40 Ligand
• Nitric Oxide Synthase Type II
• Nos2 protein, mouse
• NADPH Oxidases

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology)
• Antioxidants (pharmacology)
• Biomarkers (metabolism)
• CD40 Ligand (antagonists & inhibitors, deficiency, genetics, metabolism)
• Diabetes Mellitus, Type 2 (genetics, metabolism, physiopathology, prevention & control)
• Diet, High-Fat
• Disease Models, Animal
• Endothelium, Vascular (drug effects, metabolism, physiopathology)
• Humans
• Hyperlipidemias (genetics, metabolism, physiopathology)
• Inflammation (genetics, metabolism, physiopathology, prevention & control)
• Inflammation Mediators (metabolism)
• Interleukin-6 (metabolism)
• Lipids (blood)
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Myocardium (metabolism)
• NADPH Oxidases (metabolism)
• Nitric Oxide Synthase Type II (metabolism)
• Obesity (genetics, metabolism, physiopathology, prevention & control)
• Oxidative Stress (drug effects)
• Platelet Activation
• TNF Receptor-Associated Factor 6 (antagonists & inhibitors, metabolism)
• Vasodilation (drug effects)
• Weight Gain