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Basic Res Cardiol (2013) 108:386 DOI 10.1007/s00395-013-0386-5
ORIGINAL CONTRIBUTION
CD40L contributes to angiotensin II-induced pro-thrombotic state, vascular inammation, oxidative stress and endothelial dysfunction
Michael Hausding Kerstin Jurk Steffen Daub Swenja Krller-Schn Judith Stein
Melanie Schwenk Matthias Oelze Yuliya Mikhed Jasmin Ghaemi Kerahrodi
Sabine Kossmann Thomas Jansen Eberhard Schulz Philip Wenzel Angelika B. Reske-Kunz
Christian Becker Thomas Mnzel Stephan Grabbe Andreas Daiber
Received: 4 April 2013 / Revised: 14 August 2013 / Accepted: 6 September 2013 / Published online: 24 September 2013 Springer-Verlag Berlin Heidelberg 2013
Abstract CD40 ligand (CD40L) is involved in the vascular inltration of immune cells and pathogenesis of atherosclerosis. Additionally, T cell CD40L release causes platelet, dendritic cell and monocyte activation in thrombosis. However, the role of CD40L in angiotensin II (ATII)-driven vascular dysfunction and hypertension remains incompletely understood. We tested the hypothesis that CD40L contributes to ATII-driven vascular inammation by promoting plateletleukocyte activation, vascular inltration of immune cells and by amplifying oxidative
stress. C57BL/6 and CD40L-/- mice were infused with ATII (1 mg/kg/day for 7 days) using osmotic minipumps. Vascular function was recorded by isometric tension studies, and reactive oxygen species (ROS) were monitored in blood and heart by optical methods. Western blot, immunohistochemistry, FACS analysis and real-time RTPCR were used to analyze immune cell distribution, proinammatory cytokines, NAPDH oxidase subunits, T cell transcription factors and other genes of interest. ATII-treated CD40L-/- mice showed improved endothelial function, suppression of blood plateletmonocyte interaction (FACS), platelet thrombin generation (calibrated automated thrombography) and coagulation (bleeding time), as well as decreased oxidative stress in the aorta, heart and blood compared to wild-type mice. Moreover, ATII-treated CD40L-/- mice displayed decreased levels of TH1 cytokines released by splenic CD4? T cells (ELISA)
and lower expression levels of NOX-2, T-bet and P-selectin as well as diminished immune cell inltration in aortic tissue compared to controls. Our results demonstrate that many ATII-induced effects on vascular dysfunction, such as vascular inammation, oxidative stress and a prothrombotic state, are mediated at least in part via CD40L.
Keywords Immune cell inltration Vascular
inammation Phagocytic NADPH oxidase Platelet
activation Endothelial function Bleeding time
Introduction
CD40 ligand (CD40L, CD154) is a member of the tumor necrosis factor (TNF) family preferentially expressed on the surface of activated CD4? T cells and platelets and to a...