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CD40L contributes to angiotensin II-induced pro-thrombotic state, vascular inflammation, oxidative stress and endothelial dysfunction

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Abstract

CD40 ligand (CD40L) is involved in the vascular infiltration 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 inflammation by promoting platelet–leukocyte activation, vascular infiltration 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 RT-PCR were used to analyze immune cell distribution, pro-inflammatory cytokines, NAPDH oxidase subunits, T cell transcription factors and other genes of interest. ATII-treated CD40L−/− mice showed improved endothelial function, suppression of blood platelet–monocyte 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 infiltration in aortic tissue compared to controls. Our results demonstrate that many ATII-induced effects on vascular dysfunction, such as vascular inflammation, oxidative stress and a pro-thrombotic state, are mediated at least in part via CD40L.

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Acknowledgments

The authors acknowledge A. Karpi, P. Hölter, J. Schreiner, N. Glas, J. Rudolph, B. Mros and E. Montermann for their excellent technical assistance and Dr. J. Altmeier for her help in FACS analysis in the FACS Core Facility of the University Medical Center Mainz, Germany. We highly appreciate the contribution of our graphical artist Margot Neuser. We thank Prof. Dr. H.J. Schild and Dr. P. Stein (Institute for Immunology, University of Mainz, Germany) for providing the CD40L−/− mice. This work was supported by funds from the Federal Ministry of Education and Research (BMBF 01EO1003) to A.D., S.G., K.J., P.W., C.B. and T.M; S.K.-S., E.S., A.D. and P.W. were supported by grants of the German Research Foundation (WE 4361/3-1 and WE 4361/4-1) and T.M. holds grants from the Stiftung Mainzer Herz. Y. Mikhed holds a stipend from the International PhD Programme on the “Dynamics of Gene Regulation, Epigenetics and DNA Damage Response” from the Institute of Molecular Biology gGmbH (Mainz, Germany) funded by the Boehringer Ingelheim Foundation. This work contains parts of the thesis of S. Daub.

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Authors and Affiliations

  1. II. Medizinische Klinik, Department of Cardiology, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Langenbeckstr. 1, 55131, Mainz, Germany

    Michael Hausding, Steffen Daub, Swenja Kröller-Schön, Matthias Oelze, Yuliya Mikhed, Jasmin Ghaemi Kerahrodi, Sabine Kossmann, Thomas Jansen, Eberhard Schulz, Philip Wenzel, Thomas Münzel & Andreas Daiber

  2. Center for Thrombosis and Hemostasis (CTH), Medical Center of the Johannes Gutenberg University, Mainz, Germany

    Michael Hausding, Kerstin Jurk, Swenja Kröller-Schön, Judith Stein, Melanie Schwenk, Sabine Kossmann, Philip Wenzel & Christian Becker

  3. Department of Dermatology, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Langenbeckstr. 1, 55131, Mainz, Germany

    Judith Stein, Melanie Schwenk, Angelika B. Reske-Kunz, Christian Becker & Stephan Grabbe

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Correspondence to Stephan Grabbe or Andreas Daiber.

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T. Münzel, S. Grabbe and A. Daiber contributed equally and are joint senior authors.

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Hausding, M., Jurk, K., Daub, S. et al. CD40L contributes to angiotensin II-induced pro-thrombotic state, vascular inflammation, oxidative stress and endothelial dysfunction. Basic Res Cardiol 108, 386 (2013). https://doi.org/10.1007/s00395-013-0386-5

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  • DOI: https://doi.org/10.1007/s00395-013-0386-5

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