Project description

In Germany about 150.000 patients per year present with sepsis and approximately 56.000 of them die. Endotoxins of bacteria (e.g. LPS) are responsible for the pathogenesis of sepsis. In the state of sepsis, platelet-endothelial interaction and platelet aggregation are leading to microthrombi formation, which clot the capillaries in organs, leading to organ failure. DPP4-inhibition is a relatively new approach to treat diabetic patients by raising GLP-1 levels which leads to increased insulin secretion. Besides this DPP-4-inhibtion is able to improve survival in a model of septic mice. The impact of dipeptidyl peptidase-4-inhibition (DPP-4) or genetic deletion on vascular function and the coagulation system in a murine sepsis model will be subject of this project. Intravital microscopic imaging will be used to visualize platelet adherence to the vascular wall. Furthermore, PTT, INR, “thrombin burst”, platelet activity (FACS), total bleeding time and the formation of microthrombi in different tissues (using markers of activated platelets) will be measured to characterize the hemostatic situation. In addition, vascular function (e.g. nitric oxide, prostacyclin), proinflammatory markers (e.g. TNF-a, IL-6, IL-17 and oxidative stress will be determined to explore the influence of endothelial cells on the coagulation system. The results of my project might have high clinical impact, by defining new strategies for the treatment of septic patients. Moreover, the pathogenesis of atherothrombotic events, like coronary stenosis, are based on similar mechanisms as compared to sepsis induced platelet activation opening additional research fields of interest.

Research Interests

• The role of dipeptidyl peptidase-4 (DPP4) and glucagon-like peptide 1 (GLP 1) in the pathogenesis of sepsis
• The influence of the inhibition of dipeptidyl peptidase-4, the activity and the interaction of platelets with the endothelium

Mentor

Mentor of the Virchow-Fellow is Professor Andreas Daiber, MD, Head of the research group Molecular Cardiology at the Department of Medicine 2.

References

• Daiber A, Di Lisa F, Oelze M, Kröller-Schön S, Steven S, Schulz E, Münzel T. Crosstalk of mitochondria with NADPH oxidase via reactive oxygen and nitrogen species signalling and its role for vascular function. British journal of pharmacology. 2015.

• Steven S, Hausding M, Kröller-Schön S, Mader M, Mikhed Y, Stamm P, Zinssius E, Pfeffer A, Welschof P, Agdauletova S, Sudowe S, Li H, Oelze M, Schulz E, Klein T, Münzel T, Daiber A. Gliptin and GLP-1 analog treatment improves survival and vascular inflammation/dysfunction in animals with lipopolysaccharide-induced endotoxemia. Basic research in cardiology 110:6, 2015.

• Mikhed Y, Daiber A, Steven S. Mitochondrial Oxidative Stress, Mitochondrial DNA Damage and Their Role in Age-Related Vascular Dysfunction. International journal of molecular sciences 16:15918-15953, 2015.

• Steven S, Münzel T, Daiber A. Exploiting the Pleiotropic Antioxidant Effects of Established Drugs in Cardiovascular Disease. International journal of molecular sciences 16:18185-18223, 2015.

• Jabs A, Oelze M, Mikhed Y, Stamm P, Kroller-Schon S, Welschof P, Jansen T, Hausding M, Kopp M, Steven S, Schulz E, Stasch JP, Munzel T, Daiber A. Effect of soluble guanylyl cyclase activator and stimulator therapy on nitroglycerin-induced nitrate tolerance in rats. Vascular pharmacology, 2015.

• Schulz E, Steven S, Münzel T. Is at least one vitamin helping our vasculature? Evidence for an important role of the endothelial vitamin d receptor in regulating endothelial function and blood pressure. Hypertension 64:1187-1188,  2014.

• Kossmann S, Hu H, Steven S, Schönfelder T, Fraccarollo D, Mikhed Y, Brähler M, Knorr M, Brandt M, Karbach SH, Becker C, Oelze M, Bauersachs J, Widder J, Münzel T, Daiber A, Wenzel P. Inflammatory Monocytes Determine Endothelial Nitric Oxide Synthase Uncoupling and Nitro-oxidative Stress Induced by Angiotensin II. The Journal of biological chemistry, 2014.
  

• Kröller-Schön S, Steven S, Kossmann S, Scholz A, Daub S, Oelze M, Xia N, Hausding M, Mikhed Y, Zinssius E, Mader M, Stamm P, Treiber N, Scharffetter-Kochanek K, Li H, Schulz E, Wenzel P, Münzel T, Daiber A. Molecular mechanisms of the crosstalk between mitochondria and NADPH oxidase through reactive oxygen species-studies in white blood cells and in animal models. Antioxid Redox Signal 20:247-266, 2014.
  

• Oelze M, Kröller-Schön S, Steven S, Lubos E, Doppler C, Hausding M, Tobias S, Brochhausen C, Li H, Torzewski M, Wenzel P, Bachschmid M, Lackner KJ, Schulz E, Münzel T, Daiber A. Glutathione peroxidase-1 deficiency potentiates dysregulatory modifications of endothelial nitric oxide synthase and vascular dysfunction in aging. Hypertension 63:390-396, 2014.
  
  Lisi M, Oelze M, Dragoni S, Liuni A, Steven S, Luca MC, Stalleicken D, Münzel T, Laghi-Pasini F, Daiber A, Parker JD, Gori T; Chronic protection against ischemia and reperfusion-induced endothelial dysfunction during therapy with different organic nitrates; Clinical research in cardiology (Volume 101, Number 6 (2012), 453-459)
  
  
• Schuhmacher S, Oelze M, Bollmann F, Kleinert H, Otto C, Heeren T, Steven S, Hausding M, Knorr M, Pautz A, Reifenberg K, Schulz E, Gori T, Wenzel P, Münzel T, Daiber A; Vascular dysfunction in experimental diabetes is improved by pentaerithrityltetranitrate but not isosorbide-5-mononitrate therapy; Diabetes (Volume 60, Issue 10, October 2011, Pages 2608-16)
  
  
• Knorr M, Hausding M, Kröller-Schuhmacher S, Steven S, Oelze M, Heeren T, Scholz A, Gori T, Wenzel P, Schulz E, Daiber A, Münzel T; Nitroglycerin-Induced Endothelial Dysfunction and Tolerance Involve Adverse Phosphorylation and S-Glutathionylation of Endothelial Nitric Oxide Synthase: Beneficial Effects of Therapy With the AT1 Receptor Blocker Telmisartan; Ateriosclerosis, Thrombosis, and Vascular Biology (Volume 31, Issue 10, October 2011, Pages 2223-31)
  
  
• Jansen T, Hortmann M, Oelze M, Opitz B, Steven S, Schell R, Knorr M, Karbach S, Schuhmacher S, Wenzel P, Münzel T, Daiber A; Conversion of biliverdin to bilirubin by biliverdinreductase contributes to endothelial cell protection by heme oxygenase-1-evidence for direct and indirect antioxidant actions of bilirubin; Journal of Molecular and Cellular Cardiology (Volume 49, Issue 2, August 2010, Pages 186-195)
  
  
• Oelze M, Kröller-Schön S, Wenzel P, Otto C, Steven S, Heeren T, Stalleicken D, Münze T, Daiber A; Organische Nitrate im experimentellen Diabetes mellitus Typ 1 und in der arteriellen Hypertonie; Herz Supplement I, 36/2011 (Pages 32-40)
  
  
• Oelze M, Schuhmacher S, Scholz A, Steven S, Daiber A; Pulmonale Hypertonie-einweiteres Anwendungsgebiet für PETN; Herz Supplement II, 35/2010 (Pages 45-49)