Select languageSelect language
Institute of Physiology and Pathophysiology

Wagner Group

This page requires JavaScript for full functionality.

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).


Update

 

 

Given the current situation, we kindly ask you to abstain from visits to the institute as much as possible. However, the staff of the Institute of Physiology and Pathophysiology can still be reached by e-mail. 

 

Recent Publications

*

Amyloid, APP, and Electrical Activity of the Brain. Neuroscientist. 2020 Jun;26(3):231-251. doi: 10.1177/1073858419882619. Epub 2019 Nov 29.

*

Selective inhibition of mitochondrial respiratory complexes controls the transition of microglia into a neurotoxic phenotype in situ. Brain Behav Immun. 2020 May 21. pii: S0889-1591(20)30209-9. doi: 10.1016/j.bbi.2020.05.052. [Epub ahead of print]

*

Synchronicity of excitatory inputs drives hippocampal networks to distinct oscillatory patterns. Hippocampus. 2020 May 15. doi: 10.1002/hipo.23214. [Epub ahead of print]

*

Vascular Signaling in Allogenic Solid Organ Transplantation – The Role of Endothelial Cells. Front Physiol. 2020 May 8;11:443. doi: 10.3389/fphys.2020.00443. eCollection 2020. Review.

*

Plant "intelligence" changes nothing. EMBO Rep. 2020 May 6;21(5):e50395. doi: 10.15252/embr.202050395. Epub 2020 Apr 16.

*

Inhibition of cardiac Kv4.3 (Ito) channel isoforms by class I antiarrhythmic drugs lidocaine and mexiletine. Eur J Pharmacol. 2020 Apr 29:173159. doi: 10.1016/j.ejphar.2020.173159. [Epub ahead of print]

*

Functional association of a CD40 gene single nucleotide polymorphism with the pathogenesis of coronary heart disease. Cardiovasc Res. 2020 May 1;116(6):1214-1225. doi: 10.1093/cvr/cvz206. Epub 2019 Aug 2.

*

Risk and protective factors for post-thrombotic syndrome after deep venous thrombosis. J Vasc Surg Venous Lymphat Disord. 2020 May;8(3):390-395. doi: 10.1016/j.jvsv.2019.10.012. Epub 2019 Dec 14.

*

Marfan-Syndrom: Eine therapeutische Herausforderung für die Langzeitbehandlung (1/3). Medinlux. 2020 Apr;4:18-22. Review.

*

AAV-mediated TIMP-1 overexpression in aortic tissue reduces the severity of allograft vasculopathy in mice. J Heart Lung Transplant. 2020 Apr;39(4):389-398. doi: 10.1016/j.healun.2020.01.1338. Epub 2020 Jan 30.

*

Endothelial CD40 Mediates Microvascular von Willebrand Factor-Dependent Platelet Adhesion Inducing Inflammatory Venothrombosis in ADAMTS13 Knockout Mice. Thromb Haemost. 2020 Mar;120(3):466-476. doi: 10.1055/s-0040-1702228. Epub 2020 Mar 5.

*

Assembly of vascular smooth muscle cells in 3D aggregates provokes cellular quiescence. Exp Cell Res. 2020 Mar 1;388(1):111782. doi: 10.1016/j.yexcr.2019.111782. Epub 2019 Dec 16.

*

Mild metabolic stress is sufficient to disturb the formation of pyramidal cell ensembles during gamma oscillations. J Cereb Blood Flow Metab. 2019 Dec 16:271678X19892657. doi: 10.1177/0271678X19892657. [Epub ahead of print

*

The mitochondrial calcium uniporter is crucial for the generation of fast cortical network rhythms. J Cereb Blood Flow Metab. 2019 Nov 13:271678X19887777. doi: 10.1177/0271678X19887777. [Epub ahead of print]


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