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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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Alterations of distributed neuronal network oscillations during acute pain in freely-moving mice. IBRO Rep. 2020 Dec;9:195-206. doi: 10.1016/j.ibror.2020.08.001. eCollection 2020 Dec. Epub 2020 Aug 11.

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Neuronal gamma oscillations and activity-dependent potassium transients remain regular after depletion of microglia in postnatal cortex tissue. J Neurosci Res. 2020 Oct;98(10):1953-1967. doi: 10.1002/jnr.24689. Epub 2020 Jul 7.

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Synchronicity of excitatory inputs drives hippocampal networks to distinct oscillatory patterns. Hippocampus. 2020 Oct;30(10):1044-1057. doi: 10.1002/hipo.23214. Epub 2020 May 15.

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Multifunctional reactive MALDI matrix enabling high-lateral resolution dual polarity MS imaging and lipid C=C position-resolved MS2 imaging. Anal Chem. 2020 Sep 12. doi: 10.1021/acs.analchem.0c03150. Online ahead of print.

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VEGF-D Downregulation in CA1 Pyramidal Neurons Exerts Asymmetric Changes of Dendritic Morphology without Correlated Electrophysiological Alterations. Neuroscience. 2020 Sep 10:S0306-4522(20)30578-9. doi: 10.1016/j.neuroscience.2020.09.012. Online ahead of print.

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Anesthetics and plants: no pain, no brain, and therefore no consciousness. Protoplasma. 2020 Sep 2. doi: 10.1007/s00709-020-01550-9. Online ahead of print.

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Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing. Nat Rev Drug Discov. 2020 Sep;19(9):609-633. doi: 10.1038/s41573-020-0072-x. Epub 2020 Jul 24.

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Microglia and lipids: how metabolism controls brain innate immunity. Semin Cell Dev Biol. 2020 Aug 14;S1084-9521(19)30197-1. doi: 10.1016/j.semcdb.2020.08.001. Online ahead of print.

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GM-CSF induces noninflammatory proliferation of microglia and disturbs electrical neuronal network rhythms in situ. J Neuroinflammation. 2020 Aug 11;17(1):235. doi: 10.1186/s12974-020-01903-4.

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Inhibition of cardiac Kv4.3 (Ito) channel isoforms by class I antiarrhythmic drugs lidocaine and mexiletine. Eur J Pharmacol. 2020 Aug 5;880:173159. doi: 10.1016/j.ejphar.2020.173159. Epub 2020 Apr 29.

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Selective inhibition of mitochondrial respiratory complexes controls the transition of microglia into a neurotoxic phenotype in situ. Brain Behav Immun. 2020 Aug;88:802-814. doi: 10.1016/j.bbi.2020.05.052. Epub 2020 May 21.

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Lactate Attenuates Synaptic Transmission and Affects Brain Rhythms Featuring High Energy Expenditure. iScience. 2020 Jul 24;23(7):101316. doi: 10.1016/j.isci.2020.101316. Epub 2020 Jun 27.

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A Global Cndp1-Knock-Out Selectively Increases Renal Carnosine and Anserine Concentrations in an Age- and Gender-Specific Manner in Mice. Int J Mol Sci. 2020 Jul 10;21(14):4887. doi:10.3390/ijms21144887.

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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

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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