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Institute of Physiology and Pathophysiology

Wagner Group

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Group Members

Endothelial Cell-Platelet-Leukocyte Interaction in Vascular Remodelling: Role of CD40/CD154-Mediated Co-Stimulation

(Project C6/Hecker, SFB / Transregio 23 "Vascular Differentiation and Remodeling" Dies ist ein externer Link)

 

Pegah Khamehgir-Silz, Su-Hwan Kim (Research Training Group), Sebastian Lont, Cheryl Sultan, Andreas H. Wagner

 

CD40 is a cell surface receptor belonging to the tumour necrosis factor receptor family. It is constitutively expressed by antigen-presenting cells such as monocyte/macrophages but also by non-immune cells like endothelial cells. The CD40 ligand (CD154), originally identified as a surface marker of activated T cells, is also present on activated platelets which release numerous bioactive mediators capable of modulating innate immune cells, activating endothelial cells, and influencing systemic immune responses. In endothelial cells, CD40-CD154 interaction causes a marked increase in the expression of pro-inflammatory adhesion molecules and chemokines which, in turn, promote the homing and extravasation of T cells, namely type 1 T-helper (Th1) cells, and monocyte/macrophages. In the vessel wall, Th1 cell differentiation and activity may additionally be controlled by natural T-regulatory cells (Treg) which are frequently detected in early atherosclerotic lesions. Moreover, the transmigration of both types of lymphocytes as well as that of monocytes through the endothelial cell monolayer might be facilitated by platelets present at the endothelial cell junctions.

 

The aim of this project is to examine the relative extent by which CD40-CD154 driven endothelial cell-leukocyte, endothelial cell-platelet and/or platelet-leukocyte interactions contribute to the initiation and/or maintenance of atherosclerosis. It  focuses on the interaction of Th1 cells, Treg and monocytes with both endothelial cells and platelets as well as with each other, and primarily employs reverse genetics techniques in vitro (human cultured cells) and in vivo (mouse).


CD154 induced changes in gene expression in endothelial cells and their consequences for endothelial cell-leukocyte interaction.

Protein Oxidation in Vascular Cells as Protective Mechanism against Diabetic Angiopathy

(Projekt International Research Training Group 1874/1 "Diabetic Microvascular Complications") Dies ist ein externer Link)

 

Christoph Hangel, Tanja Wiedenmann, Andreas H. Wagner, Markus Hecker

 

It is virtually certain that reactive oxygen (ROS) and nitrogen (RNS) species contribute to diabetic vascular lesions. Hyperglycaemia, for example, leads to the protein carbonylation and nitration by increased oxidative and nitrosative stress, respectively. Glucose-derived dicarbonyl oxidation products such as methylglyoxal (MG) increase mitochondrial formation of superoxide anions (O2) which can react with nitrogen monoxide (NO) to form peroxynitrite (nitration) in endothelial cells, and, via hydrogen peroxide (H2O2) and the Fe2+-dependent Fenton reaction, hydroxyl radicals (carbonylation), respectively.


This project aims at analysing the role of oxidative protein modifications as a potential protective mechanism of vascular cells against late diabetic lesions, and diabetic macroangiopathy in particular.

Inhibition of Aortic Elastolysis by Decoy Oligodeoxynucleotides-Mediated Inhibition of Transcription of Matrix Metalloproteinases in the Fibrillin-1 Deficient Mouse mgR/mgR (Marfan model)

(supported by the B. Braun-Stiftung, Melsungen Dies ist ein externer Link)

 

Anca Remes, Andreas H. Wagner
Clinic for Cardiac Surgery, Heidelberg University Hospital: Rawa Arif, Klaus Kallenbach

 

Quite often vascular changes associated with the Marfan syndrome, such as aortic aneurysms or aortic dissections, threaten the lifes of those afflicted already in childhood. To date no causal therapy of this genetic disease of the connective tissue exists. The vascular component of the Marfan syndrome is pathophysiologically characterised by an abnormally high activity of matrix metalloproteinases (MMPs) in smooth muscle cells of the aortic wall. This group of enzymes causes elastolysis in the aortic media thereby contributing to the progressing destablisation of the vascular wall.

The homozygose fibrillin-1 deficient mouse (mgR/mgR) is an accepted small animal model for the Marfan syndrome. Similar to patients with the Marfan syndrome, it shows an elevated MMP activity in the smooth muscle cells of the aortic wall in combination with an age-dependent increased fragmentation of elastic fibres. Employing the Marfan mouse model, we want to inhibit the expression of MMP, and as a consequence reduce their activity, by incubating aortic fragments with decoy oligodeoxynucleotides (dODN) ex vivo

Gene Therapy of Transplantation Vasculopathy

(supported by the Dietmar Hopp Stiftung gGmbH, St. Leon-RotDies ist ein externer Link)

 

Andreas H. Wagner
Clinic for Cardiac Surgery, Heidelberg University Hospital: Rawa Arif, Klaus Kallenbach
Initernal Medicine III, Division of Cardiology, Angiology and Pneumology, Heidelberg University Hospital: Oliver Müller

 

Project description on the website of the Dietmar Hopp Foundation (in German).


Recent Publications

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Hypertension-evoked RhoA activity in vascular smooth muscle cells requires RGS5. FASEB J. 2017 Dec 5. pii: fj.201700384RR. doi: 10.1096/fj.201700384RR. [Epub ahead of print]

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Modulation of glutathione peroxidase activity by age-dependent carbonylation in glomeruli of diabetic mice. J Diabetes Complications. 2017 Nov 22. pii: S1056-8727(17)31094-2. doi: 10.1016/j.jdiacomp.2017.11.007. [Epub ahead of print]

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Sensitive mass spectrometric assay for determination of 15-deoxy-Δ12,14-prostaglandin J2 and its application in human plasma samples of patients with diabetes. Anal Bioanal Chem. 2017 Nov 16. doi: 10.1007/s00216-017-0748-1. [Epub ahead of print]

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Role of protein carbonylation in diabetes. J Inherit Metab Dis. 2017 Nov 6. doi: 10.1007/s10545-017-0104-9. [Epub ahead of print]

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AP-1 Oligodeoxynucleotides Reduce Aortic Elastolysis in a Murine Model of Marfan Syndrome. Mol Ther Nucleic Acids. 2017 Dec 15; 9: 69–79. Epub 2017 Sep 20. doi: 10.1016/j.omtn.2017.08.014

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Allosteric inhibition of carnosinase (CN1) by inducing a conformational shift. J Enzyme Inhib Med Chem. 2017 Dec;32(1):1102-1110. doi: 10.1080/14756366.2017.1355793.

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Transcription factor decoy technology: a therapeutic update. Biochem Pharmacol. 2017 Nov 15;144:29-34. doi: 10.1016/j.bcp.2017.06.122. Epub 2017 Jun 19. Review.

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Local oxygen homeostasis during various neuronal network activity states in the mouse hippocampus. J Cereb Blood Flow Metab. 2017 Nov 3; 271678X17740091. doi: 10.1177/0271678X17740091

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Subtype-specific differentiation of cardiac pacemaker cell clusters from human induced pluripotent stem cells. Stem Cell Res Ther. 2017 Oct 16;8(1):229. doi: 10.1186/s13287-017-0681-4.

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Heteromeric channels formed by TRPC1, TRPC4 and TRPC5 define hippocampal synaptic transmission and working memory. EMBO J. 2017 Sep 15;36(18):2770-2789. doi: 10.15252/embj.201696369. Epub 2017 Aug 8


Institute of
Physiology and Pathophysiology

Heidelberg University

Im Neuenheimer Feld 326

69120 Heidelberg

Germany

Phone:+49 6221 54-4056
Fax:+49 6221 54-6364
E-mail:susanne.bechtel@
physiologie.uni-heidelberg.de