Marco Witkowski
Charité
Network
Latest external collaboration on country level. Dive into details by clicking on the dots.
Publication
Featured researches published by Marco Witkowski.
Trends in Cardiovascular Medicine | 2016
Marco Witkowski; Ulf Landmesser; Ursula Rauch
Due to its receptor activity for factor VII, tissue factor (TF) is primary initiator of the blood coagulation cascade and ensures rapid hemostasis in case of organ damage. Inflammatory cytokines, such as tumor necrosis factor-α or interleukins, strongly induce expression of both full-length TF as well as the alternatively spliced TF in endothelial and blood cells. Beyond its role in hemostasis, TF also has signaling activity and promotes pleiotropic inflammatory responses via protease-activated receptors in concert with other coagulation factors. Alteration of TF expression and TF alternative splicing provides an effective means to change the endothelial phenotype and modulate inflammatory responses of the vessel.
Science | 2016
Penelope Pelczar; Mario Witkowski; Laura Garcia Perez; Jan Kempski; Anna G. Hammel; Leonie Brockmann; Dörte Kleinschmidt; Sandra Wende; Cathleen Haueis; Tanja Bedke; Marco Witkowski; Susanne Krasemann; Stefan Steurer; Carmen J. Booth; Philipp Busch; Alexandra König; Ursula Rauch; Daniel Benten; Jakob R. Izbicki; Thomas Rösch; Ansgar W. Lohse; Till Strowig; Nicola Gagliani; Richard A. Flavell; Samuel Huber
Interleukin-22 binding protein (IL-22BP) drives inflammatory bowel disease by sopping up the tissue-protective protein IL-22. Intestinal inflammation can impair mucosal healing, thereby establishing a vicious cycle leading to chronic inflammatory bowel disease (IBD). However, the signaling networks driving chronic inflammation remain unclear. Here we report that CD4+ T cells isolated from patients with IBD produce high levels of interleukin-22 binding protein (IL-22BP), the endogenous inhibitor of the tissue-protective cytokine IL-22. Using mouse models, we demonstrate that IBD development requires T cell–derived IL-22BP. Lastly, intestinal CD4+ T cells isolated from IBD patients responsive to treatment with antibodies against tumor necrosis factor–α (anti–TNF-α), the most effective known IBD therapy, exhibited reduced amounts of IL-22BP expression but still expressed IL-22. Our findings suggest that anti–TNF-α therapy may act at least in part by suppressing IL-22BP and point toward a more specific potential therapy for IBD.
Thrombosis Research | 2016
Yohei Hisada; Wyeth Alexander; Raj S. Kasthuri; Peter M. Voorhees; Fariborz Mobarrez; Angela M. Taylor; Coleen A. McNamara; Håkan Wallén; Marco Witkowski; Nigel S. Key; Ursula Rauch; Nigel Mackman
Thrombosis is a leading cause of morbidity and mortality. Detection of a prothrombotic state using biomarkers would be of great benefit to identify patients at risk of thrombosis that would benefit from thromboprophylaxis. Tissue factor (TF) is a highly procoagulant protein that under normal conditions is not present in the blood. However, increased levels of TF in the blood in the form of microparticles (MPs) (also called extracellular vesicles) are observed under various pathological conditions. In this review, we will discuss studies that have measured MP-TF activity in a variety of diseases using two similar FXa generation assay. One of the most robust signals for MP-TF activity (16-26 fold higher than healthy controls) is observed in pancreatic cancer patients with venous thromboembolism. In this case, the TF+ MPs appear to be derived from the cancer cells. Surprisingly, cirrhosis and acute liver injury are associated with 17-fold and 38-fold increases in MP-TF activity, respectively. Based on mouse models, we speculate that the TF+ MPs are derived from hepatocytes. More modest increases are observed in patients with urinary tract infections (6-fold) and in a human endotoxemia model (9-fold) where monocytes are the likely source of the TF+ MPs. Finally, there is no increase in MP-TF activity in the majority of cardiovascular disease patients. These studies indicate that MP-TF activity may be a useful biomarker to identify patients with particular diseases that have an increased risk of thrombosis.
Arteriosclerosis, Thrombosis, and Vascular Biology | 2016
Marco Witkowski; Alice Weithauser; Termeh Tabaraie; Daniel Steffens; Nicolle Kränkel; Mario Witkowski; Bernd Stratmann; Diethelm Tschoepe; Ulf Landmesser; Ursula Rauch-Kroehnert
Objective— Diabetes mellitus involves vascular inflammatory processes and is a main contributor to cardiovascular mortality. Notably, heightened levels of circulating tissue factor (TF) account for the increased thrombogenicity and put those patients at risk for thromboembolic events. Here, we sought to investigate the role of micro-RNA (miR)–driven TF expression and thrombogenicity in diabetes mellitus. Approach and Results— Plasma samples of patients with diabetes mellitus were analyzed for TF protein and activity as well as miR-126 expression before and after optimization of the antidiabetic treatment. We found low miR-126 levels to be associated with markedly increased TF protein and TF-mediated thrombogenicity. Reduced miR-126 expression was accompanied by increased vascular inflammation as evident from the levels of vascular adhesion molecule-1 and fibrinogen, as well as leukocyte counts. With optimization of the antidiabetic treatment miR-126 levels increased and thrombogenicity was reduced. Using a luciferase reporter system, we demonstrated miR-126 to directly bind to the F3-3′-untranslated region, thereby reducing TF expression both on mRNA and on protein levels in human microvascular endothelial cells as well as TF mRNA and activity in monocytes. Conclusions— Circulating miR-126 exhibits antithrombotic properties via regulating post-transcriptional TF expression, thereby impacting the hemostatic balance of the vasculature in diabetes mellitus.
Critical Care Medicine | 2015
Marco Witkowski; Hans-Christian Mochmann; Ursula Rauch; Wulf Knie; Ulf Landmesser; Carsten Skurk
Objective:To report a case of intra-arterial amiodarone injection in a hemodynamically unstable patient leading to acute vessel occlusion and a subsequent compartment syndrome. Design:Case report. Setting:Prehospital setting, emergency department and ICU of a university hospital. Patient:A 58-year-old woman presenting with a ventricular tachycardia of 190 beats/min was administered amiodarone through an accidently placed arterial access in the left cubital fossa. Quickly, the woman developed clinical signs of an acute arterial occlusion. Interventions:Immediate left brachial artery angiography with subsequent thrombectomy was performed. Measurements and Main Results:A thrombotic occlusion at the injection side was found, which was immediately recanalized by thrombus aspiration. In addition to anticoagulation and an adenosine diphosphate-antagonist an adjunct therapy with vasodilators and gpIIb/IIIa inhibitors was given and repetitive duplex sonography confirmed arterial flow. However, despite restoration of blood flow the patient developed a severe compartment syndrome of the arm and had to receive multistep surgical interventions. Conclusions:This is the first report of an acute thrombotic vessel occlusion leading to a compartment syndrome upon accidental intra-arterial injection of amiodarone in an emergency setting. In the hemodynamically unstable patient healthcare providers should be aware of arterial miscanulation and its consequences. Upon intra-arterial injection, a direct antithrombotic and vasodilative therapy should be administered via the initially misplaced arterial access, which may include a gpIIb/IIIa inhibitor.
Current Pharmaceutical Design | 2016
Alice Weithauser; Marco Witkowski; Ursula Rauch
Protease-activated receptors (PARs) are a unique group of four G-protein coupled receptors. They are widely expressed within the cardiovascular system and the heart. PARs are activated via cleavage by serine proteases. In vitro and in vivo studies showed that the activation of PAR1 and PAR2 plays a crucial role in virus induced inflammatory diseases. The receptors enable cells to recognize pathogen-derived changes in the extracellular environment. An infection with Coxsackie-virus B3 (CVB3) can cause myocarditis. Recent studies have been shown that PAR1 signaling enhanced the antiviral innate immune response via interferon β (IFNβ) and thus limited the virus replication and cardiac damage. In contrast, PAR2 signaling decreased the antiviral innate immune response via IFNβ und thus increased the virus replication, which caused severe myocarditis. Along with CVB3 other viruses such as influenza A virus (IAV) and herpes simplex virus (HSV) can induce myocarditis. The role of PAR signaling in IAV infections is contrarily discussed. During HSV infections PARs facilitate the virus infection of the host cell. These studies show that PARs might be interesting drug targets for the treatment of virus infections and inflammatory heart diseases. First studies with PAR agonists, antagonists, and serine protease inhibitors have been conducted in mice. The inhibition of thrombin the main PAR1 activating protease decreased the IFNβ response and increased the virus replication in CVB3-induced myocarditis. This indicates that further studies with direct PAR agonists and antagonists are needed to determine whether PARs are useful drug targets for the therapy of virus-induced heart diseases.
Seminars in Immunopathology | 2018
Mario Witkowski; Marco Witkowski; Nicola Gagliani; Samuel Huber
The mucosal immune system and the microbiota in the intestinal tract have recently been shown to play a key role in the pathogenesis of inflammatory bowel disease (IBD). Both of these can be influenced by food. Thus, we propose dietary intervention as a therapeutic option for IBD. In this review, we discuss the interaction of the intestinal mucosal immune system and the intestinal microbiota in the context of IBD. In addition, we discuss the impact of food components on immune responses in IBD. Finally, we address the current evidence of how this interaction (i.e., immune system–microbiota) can be modulated by food components, pre/probiotics, and fecal microbiota transplantation (FMT) and how these approaches can support intestinal homeostasis. By gathering the vast amount of literature available on the impact of food on IBD, we aim to distinguish between scientifically sound data and theories, which have not been included in this review.
Circulation | 2015
Julian Friebel; Marco Witkowski; Ursula Rauch
Atherosclerosis is characterized as a chronic inflammatory disease. The complex network of both innate and adaptive immunity plays a significant role in the development and progression of atherosclerotic plaques. Rupture or erosion of these uring the past decades several attempts have been made to reduce cardiovascular morbidity and mortality. Unfortunately, a high disease burden still covers the developed world and is rapidly emerging in the developing countries, with all the characteristics of an epidemic. Despite intensive work in trying to prevent post-event pathological remodeling and many efforts made to improve patients’ outcomes, the data are sobering.1,2 Therefore, prevention of major D
Cardiovascular Diabetology | 2018
Marco Witkowski; Termeh Tabaraie; Daniel Steffens; Julian Friebel; Andrea Dörner; Carsten Skurk; Mario Witkowski; Bernd Stratmann; Diethelm Tschoepe; Ulf Landmesser; Ursula Rauch
BackgroundDiabetes mellitus is characterized by chronic vascular disorder and presents a main risk factor for cardiovascular mortality. In particular, hyperglycaemia and inflammatory cytokines induce vascular circulating tissue factor (TF) that promotes pro-thrombotic conditions in diabetes. It has recently become evident that alterations of the post-transcriptional regulation of TF via specific microRNA(miR)s, such as miR-126, contribute to the pathogenesis of diabetes and its complications. The endothelial miR-19a is involved in vascular homeostasis and atheroprotection. However, its role in diabetes-related thrombogenicity is unknown. Understanding miR-networks regulating procoagulability in diabetes may help to develop new treatment options preventing vascular complications.Methods and resultsPlasma of 44 patients with known diabetes was assessed for the expression of miR-19a, TF protein, TF activity, and markers for vascular inflammation. High miR-19a expression was associated with reduced TF protein, TF-mediated procoagulability, and vascular inflammation based on expression of vascular adhesion molecule-1 and leukocyte count. We found plasma expression of miR-19a to strongly correlate with miR-126. miR-19a reduced the TF expression on mRNA and protein level in human microvascular endothelial cells (HMEC) as well as TF activity in human monocytes (THP-1), while anti-miR-19a increased the TF expression. Interestingly, miR-19a induced VCAM expression in HMEC. However, miR-19a and miR-126 co-transfection reduced total endothelial VCAM expression and exhibited additive inhibition of a luciferase reporter construct containing the F3 3′UTR.ConclusionsWhile both miRs have differential functions on endothelial VCAM expression, miR-19a and miR-126 cooperate to exhibit anti-thrombotic properties via regulating vascular TF expression. Modulating the post-transcriptional control of TF in diabetes may provide a future anti-thrombotic and anti-inflammatory therapy.
Cardiovascular Diabetology | 2015
Claudia Schuette; Daniel Steffens; Marco Witkowski; Caroline Stellbaum; Peter Bobbert; Heinz-Peter Schultheiss; Ursula Rauch