Background: Dipeptidyl peptidase [DPP]-4 inhibitors are a new class of drug for the treatment of ... more Background: Dipeptidyl peptidase [DPP]-4 inhibitors are a new class of drug for the treatment of hyperglycemia and recent studies revealed anti-inflammatory effects of these gliptins in experimenta...
Vascular oxidative stress, inflammation, and subsequent endothelial dysfunction are consequences ... more Vascular oxidative stress, inflammation, and subsequent endothelial dysfunction are consequences of traditional cardiovascular risk factors, all of which contribute to cardiovascular disease. Environmental stressors, such as traffic noise and air pollution, may also facilitate the development and progression of cardiovascular and metabolic diseases. In our previous studies, we investigated the influence of aircraft noise exposure on molecular mechanisms, identifying oxidative stress and inflammation as central players in mediating vascular function. The present study investigates the role of heme oxygenase-1 (HO-1) as an antioxidant response preventing vascular consequences following exposure to aircraft noise. C57BL/6J mice were treated with the HO-1 inducer hemin (25 mg/kg i.p.) or the NRF2 activator dimethyl fumarate (DMF, 20 mg/kg p.o.). During therapy, the animals were exposed to noise at a maximum sound pressure level of 85 dB(A) and a mean sound pressure level of 72 dB(A). Ou...
Oxidative stress plays a key role for the development of cardiovascular, metabolic, and neurodege... more Oxidative stress plays a key role for the development of cardiovascular, metabolic, and neurodegenerative disease. This concept has been proven by using the approach of genetic deletion of reactive oxygen and nitrogen species (RONS) producing, pro-oxidant enzymes as well as by the overexpression of RONS detoxifying, antioxidant enzymes leading to an amelioration of the severity of diseases. Vice versa, the development and progression of cardiovascular diseases is aggravated by overexpression of RONS producing enzymes as well as deletion of RONS detoxifying enzymes. We have previously identified cross talk mechanisms between different sources of RONS, which can amplify the oxidative stress-mediated damage. Here, the pathways and potential mechanisms leading to this cross talk are analyzed in detail and highlighted by selected examples from the current literature and own data including hypoxia, angiotensin II (AT-II)-induced hypertension, nitrate tolerance, aging, and others. The gene...
Reactive oxygen and nitrogen species (RONS) cause oxidative damage, which is associated with endo... more Reactive oxygen and nitrogen species (RONS) cause oxidative damage, which is associated with endothelial dysfunction and cardiovascular disease, but may also contribute to redox signaling. Therefore, their precise detection is important for the evaluation of disease mechanisms. Here, we compared three different methods for the detection of 3-nitrotyrosine (3-NT), a marker of nitro-oxidative stress, in biological samples. Nitrated proteins were generated by incubation with peroxynitrite or 3-morpholino sydnonimine (Sin-1) and subjected to total hydrolysis using pronase, a mixture of different proteases. The 3-NT was then separated by high performance liquid chromatography (HPLC) and quantified by electrochemical detection (ECD, CoulArray) and compared to classical methods, namely enzyme-linked immunosorbent assay (ELISA) and dot blot analysis using specific 3-NT antibodies. Calibration curves for authentic 3-NT (detection limit 10 nM) and a concentration-response pattern for 3-NT obt...
Background: Reactive oxygen and nitrogen species (RONS such as H2O2, nitric oxide) are generated ... more Background: Reactive oxygen and nitrogen species (RONS such as H2O2, nitric oxide) are generated within the organism. Whereas physiological formation rates confer redox regulation of essential cellular functions and provide the basis for adaptive stress responses, their excessive formation contributes to impaired cellular function or even cell death, organ dysfunction and severe disease phenotypes of the entire organism. Therefore, quantification of RONS formation and knowledge of their tissue/cell/compartment-specific distribution is of great biological and clinical importance. Methods: Here, we used a high-performance/pressure liquid chromatography (HPLC) assay to quantify the superoxide-specific oxidation product of the mitochondria-targeted fluorescence dye triphenylphosphonium-linked hydroethidium (mitoSOX) in biochemical systems and three animal models with established oxidative stress. Type 1 diabetes (single injection of streptozotocin), hypertension (infusion of angiotensin...
The Global Burden of Disease Study identified cardiovascular risk factors as leading causes of gl... more The Global Burden of Disease Study identified cardiovascular risk factors as leading causes of global deaths and life years lost. Endothelial dysfunction represents a pathomechanism that is associated with most of these risk factors and stressors, and represents an early (subclinical) marker/predictor of atherosclerosis. Oxidative stress is a trigger of endothelial dysfunction and it is a hall-mark of cardiovascular diseases and of the risk factors/stressors that are responsible for their initiation. Endothelial function is largely based on endothelial nitric oxide synthase (eNOS) function and activity. Likewise, oxidative stress can lead to the loss of eNOS activity or even “uncoupling” of the enzyme by adverse regulation of well-defined “redox switches” in eNOS itself or up-/down-stream signaling molecules. Of note, not only eNOS function and activity in the endothelium are essential for vascular integrity and homeostasis, but also eNOS in perivascular adipose tissue plays an impo...
Aims CD40 ligand (CD40L) signaling controls vascular oxidative stress and related dysfunction in ... more Aims CD40 ligand (CD40L) signaling controls vascular oxidative stress and related dysfunction in angiotensin-II-induced arterial hypertension by regulating vascular immune cell recruitment and platelet activation. Here we investigated the role of CD40L in experimental hyperlipidemia. Methods and results Male wild type and CD40L−/− mice (C57BL/6 background) were subjected to high fat diet for sixteen weeks. Weight, cholesterol, HDL, and LDL levels, endothelial function (isometric tension recording), oxidative stress (NADPH oxidase expression, dihydroethidium fluorescence) and inflammatory parameters (inducible nitric oxide synthase, interleukin-6 expression) were assessed. CD40L expression, weight, leptin and lipids were increased, and endothelial dysfunction, oxidative stress and inflammation were more pronounced in wild type mice on a high fat diet, all of which was almost normalized by CD40L deficiency. Similar results were obtained in diabetic db/db mice with CD40/TRAF6 inhibitor...
Non-alcoholic steatohepatitis (NASH) is characterized by steatosis, panlobular inflammation, live... more Non-alcoholic steatohepatitis (NASH) is characterized by steatosis, panlobular inflammation, liver fibrosis and increased cardiovascular mortality. Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) are indirect glucagon like peptide 1 (GLP-1) agonists with antidiabetic and anti-inflammatory activity, used for the treatment of type 2 diabetes. Their potential and underlying mechanisms to treat metabolic liver inflammation and fibrosis as well as the associated vascular dysfunction remain to be explored. In the methionine/choline deficient (MCD) diet and Mdr2-/- models of NASH and liver fibrosis, treatment with sitagliptin and linagliptin significantly decreased parameters of steatosis and inflammation, which was accompanied by suppression of hepatic transcripts levels reflecting metabolic inflammation and fibrosis like SREBP-1c, FAS, TNFα, iNOS, α-SMA, Col1α1 and MMP-12. Moreover, gliptins reduced the number of liver infiltrating CD11b+Ly6Chi proinflammatory monocytes/macrophages ...
The European Cooperation in Science and Technology (COST) provides an ideal framework to establis... more The European Cooperation in Science and Technology (COST) provides an ideal framework to establish multi-disciplinary research networks. COST Action BM1203 (EU-ROS) represents a consortium of researchers from different disciplines who are dedicated to providing new insights and tools for better understanding redox biology and medicine and, in the long run, to finding new therapeutic strategies to target dysregulated redox processes in various diseases. This report highlights the major achievements of EU-ROS as well as research updates and new perspectives arising from its members. The EU-ROS consortium comprised more than 140 active members who worked together for four years on the topics briefly described below. The formation of reactive oxygen and nitrogen species (RONS) is an established hallmark of our aerobic environment and metabolism but RONS also act as messengers via redox regulation of essential cellular processes. The fact that many diseases have been found to be associat...
Epidemiological studies indicate that traffic noise increases the incidence of coronary artery di... more Epidemiological studies indicate that traffic noise increases the incidence of coronary artery disease, hypertension and stroke. The underlying mechanisms remain largely unknown. Field studies with nighttime noise exposure demonstrate that aircraft noise leads to vascular dysfunction, which is markedly improved by vitamin C, suggesting a key role of oxidative stress in causing this phenomenon. We developed a novel animal model to study the vascular consequences of aircraft noise exposure. Peak sound levels of 85 and mean sound level of 72 dBA applied by loudspeakers for 4 days caused an increase in systolic blood pressure, plasma noradrenaline and angiotensin II levels and induced endothelial dysfunction. Noise increased eNOS expression but reduced vascular NO levels because of eNOS uncoupling. Noise increased circulating levels of nitrotyrosine, interleukine-6 and vascular expression of the NADPH oxidase subunit Nox2, nitrotyrosine-positive proteins and of endothelin-1. FACS analys...
Objective. Oxidative stress and endothelial dysfunction contribute to pulmonary arterial hyperten... more Objective. Oxidative stress and endothelial dysfunction contribute to pulmonary arterial hypertension (PAH). The role of the nitrovasodilator pentaerythritol tetranitrate (PETN) on endothelial function and oxidative stress in PAH has not yet been defined. Methods and Results. PAH was induced by monocrotaline (MCT, i.v.) in Wistar rats. Low (30 mg/kg; MCT30), middle (40 mg/kg; MCT40), or high (60 mg/kg; MCT60) dose of MCT for 14, 28, and 42 d was used. MCT induced endothelial dysfunction, pulmonary vascular wall thickening, and fibrosis, as well as protein tyrosine nitration. Pulmonary arterial pressure and heart/body and lung/body weight ratio were increased in MCT40 rats (28 d) and reduced by oral PETN (10 mg/kg, 24 d) therapy. Oxidative stress in the vascular wall, in the heart, and in whole blood as well as vascular endothelin-1 signaling was increased in MCT40-treated rats and normalized by PETN therapy, likely by upregulation of heme oxygenase-1 (HO-1). PETN therapy improved en...
Excessive inflammation in sepsis causes microvascular thrombosis and thrombocytopenia associated ... more Excessive inflammation in sepsis causes microvascular thrombosis and thrombocytopenia associated with organ dysfunction and high mortality. The present studies aimed to investigate whether dipeptidyl peptidase-4 (DPP-4) inhibition and supplementation with glucagon-like peptide-1 (GLP-1) analogues improves endotoxaemia-associated microvascular thrombosis via immunomodulatory effects. Endotoxaemia was induced in C57BL/6 J mice by single injection of lipopolysaccharide (LPS) (17.5 for survival and 10 mg/kg for all other studies). For survival studies therapy was started 6 h after LPS injection. For all other studies drugs were administrated 48 h prior to LPS treatment. Endotoxaemic control mice showed severe thrombocytopenia, microvascular thrombosis in the pulmonary circulation (fluorescence imaging), increased lactate dehydrogenase (LDH)-activity, endothelial dysfunction and increased markers of inflammation in the aorta and whole blood (e.g. leukocyte-dependent oxidative burst, nitr...
Nitroglycerin (GTN) and other organic nitrates are widely used vasodilators. Their side effects a... more Nitroglycerin (GTN) and other organic nitrates are widely used vasodilators. Their side effects are development of nitrate tolerance and endothelial dysfunction. Given the potential of GTN to induce nitro-oxidative stress, we investigated the interaction between nitro-oxidative DNA damage and vascular dysfunction in experimental nitrate tolerance. Cultured endothelial hybridoma cells (EA.hy 926) and Wistar rats were treated with GTN (ex vivo: 10-1000 µM; in vivo: 10, 20 and 50 mg/kg/day for 3 days, s.c.). The level of DNA strand breaks, 8-oxoguanine and O (6)-methylguanine DNA adducts was determined by Comet assay, dot blot and immunohistochemistry. Vascular function was determined by isometric tension recording. DNA adducts and strand breaks were induced by GTN in cells in vitro in a concentration-dependent manner. GTN in vivo administration leads to endothelial dysfunction, nitrate tolerance, aortic and cardiac oxidative stress, formation of DNA adducts, stabilization of p53 and a...
Cardiovascular diseases are major contributors to global deaths and disability-adjusted life year... more Cardiovascular diseases are major contributors to global deaths and disability-adjusted life years, with hypertension as a significant risk factor for all cause death. The endothelium that lines the inner wall of the vasculature regulates essential haemostatic functions such as regulation of the vascular tone, circulation of blood cells, inflammation and platelet activity. Endothelial dysfunction is an early predictor of atherosclerosis and future cardiovascular events. We review the prognostic value of measurements of endothelial function, the clinical techniques for its determination, mechanisms leading to endothelial dysfunction and the therapeutic treatment of endothelial dysfunction. Since vascular oxidative stress and inflammation are major determinants of endothelial function, we also address current antioxidant and anti-inflammatory therapies. In light of recent data that speak against the prognostic value of endothelial function in healthy human cohorts, we also discuss alt...
Introduction: Sepsis is an inflammatory state. Proinflammatory enzymes like inducible-NO Synthase... more Introduction: Sepsis is an inflammatory state. Proinflammatory enzymes like inducible-NO Synthase (iNOS) and NADPH-Oxidase (NOX) are activated and influence endothelial function via oxidative and nitrosative stress. Inhibition of dipeptidyl-peptidase 4 (DPP4i) is a new approach to treat diabetic patients. Matubara et al. (Circulation, 2012) showed a positive influence of DPP4i on endothelial function in an animal model Hypothesis: DPP4 inhibition influences endothelial function, hemostasis and survival in a rodent model of septic shock Methods: C57/BL6j mice were pretreated with different DPP4i (linagliptin, sitagliptin) and GLP-1-analogue (GLP1a) liraglutide for 3 days. Aorta and heart tissue was used for western-blotting and rtPCR. Blood was examined for coagulation parameters (aPTT, PT), cell count and oxidative stress Results: Treatment with DPP4i and GLP1-a improved survival and blood pressure of septic animals significantly. LPS-induced oxidative stress and nitrosylated hemoglobin (Hb-NO) levels wer...
International journal of molecular sciences, Jan 5, 2015
Cardiovascular disease is a leading cause of death and reduced quality of life worldwide. Arteria... more Cardiovascular disease is a leading cause of death and reduced quality of life worldwide. Arterial vessels are a primary target for endothelial dysfunction and atherosclerosis, which is accompanied or even driven by increased oxidative stress. Recent research in this field identified different sources of reactive oxygen and nitrogen species contributing to the pathogenesis of endothelial dysfunction. According to lessons from the past, improvement of endothelial function and prevention of cardiovascular disease by systemic, unspecific, oral antioxidant therapy are obviously too simplistic an approach. Source- and cell organelle-specific antioxidants as well as activators of intrinsic antioxidant defense systems might be more promising. Since basic research demonstrated the contribution of different inflammatory cells to vascular oxidative stress and clinical trials identified chronic inflammatory disorders as risk factors for cardiovascular events, atherosclerosis and cardiovascular...
Background: Dipeptidyl peptidase [DPP]-4 inhibitors are a new class of drug for the treatment of ... more Background: Dipeptidyl peptidase [DPP]-4 inhibitors are a new class of drug for the treatment of hyperglycemia and recent studies revealed anti-inflammatory effects of these gliptins in experimenta...
Vascular oxidative stress, inflammation, and subsequent endothelial dysfunction are consequences ... more Vascular oxidative stress, inflammation, and subsequent endothelial dysfunction are consequences of traditional cardiovascular risk factors, all of which contribute to cardiovascular disease. Environmental stressors, such as traffic noise and air pollution, may also facilitate the development and progression of cardiovascular and metabolic diseases. In our previous studies, we investigated the influence of aircraft noise exposure on molecular mechanisms, identifying oxidative stress and inflammation as central players in mediating vascular function. The present study investigates the role of heme oxygenase-1 (HO-1) as an antioxidant response preventing vascular consequences following exposure to aircraft noise. C57BL/6J mice were treated with the HO-1 inducer hemin (25 mg/kg i.p.) or the NRF2 activator dimethyl fumarate (DMF, 20 mg/kg p.o.). During therapy, the animals were exposed to noise at a maximum sound pressure level of 85 dB(A) and a mean sound pressure level of 72 dB(A). Ou...
Oxidative stress plays a key role for the development of cardiovascular, metabolic, and neurodege... more Oxidative stress plays a key role for the development of cardiovascular, metabolic, and neurodegenerative disease. This concept has been proven by using the approach of genetic deletion of reactive oxygen and nitrogen species (RONS) producing, pro-oxidant enzymes as well as by the overexpression of RONS detoxifying, antioxidant enzymes leading to an amelioration of the severity of diseases. Vice versa, the development and progression of cardiovascular diseases is aggravated by overexpression of RONS producing enzymes as well as deletion of RONS detoxifying enzymes. We have previously identified cross talk mechanisms between different sources of RONS, which can amplify the oxidative stress-mediated damage. Here, the pathways and potential mechanisms leading to this cross talk are analyzed in detail and highlighted by selected examples from the current literature and own data including hypoxia, angiotensin II (AT-II)-induced hypertension, nitrate tolerance, aging, and others. The gene...
Reactive oxygen and nitrogen species (RONS) cause oxidative damage, which is associated with endo... more Reactive oxygen and nitrogen species (RONS) cause oxidative damage, which is associated with endothelial dysfunction and cardiovascular disease, but may also contribute to redox signaling. Therefore, their precise detection is important for the evaluation of disease mechanisms. Here, we compared three different methods for the detection of 3-nitrotyrosine (3-NT), a marker of nitro-oxidative stress, in biological samples. Nitrated proteins were generated by incubation with peroxynitrite or 3-morpholino sydnonimine (Sin-1) and subjected to total hydrolysis using pronase, a mixture of different proteases. The 3-NT was then separated by high performance liquid chromatography (HPLC) and quantified by electrochemical detection (ECD, CoulArray) and compared to classical methods, namely enzyme-linked immunosorbent assay (ELISA) and dot blot analysis using specific 3-NT antibodies. Calibration curves for authentic 3-NT (detection limit 10 nM) and a concentration-response pattern for 3-NT obt...
Background: Reactive oxygen and nitrogen species (RONS such as H2O2, nitric oxide) are generated ... more Background: Reactive oxygen and nitrogen species (RONS such as H2O2, nitric oxide) are generated within the organism. Whereas physiological formation rates confer redox regulation of essential cellular functions and provide the basis for adaptive stress responses, their excessive formation contributes to impaired cellular function or even cell death, organ dysfunction and severe disease phenotypes of the entire organism. Therefore, quantification of RONS formation and knowledge of their tissue/cell/compartment-specific distribution is of great biological and clinical importance. Methods: Here, we used a high-performance/pressure liquid chromatography (HPLC) assay to quantify the superoxide-specific oxidation product of the mitochondria-targeted fluorescence dye triphenylphosphonium-linked hydroethidium (mitoSOX) in biochemical systems and three animal models with established oxidative stress. Type 1 diabetes (single injection of streptozotocin), hypertension (infusion of angiotensin...
The Global Burden of Disease Study identified cardiovascular risk factors as leading causes of gl... more The Global Burden of Disease Study identified cardiovascular risk factors as leading causes of global deaths and life years lost. Endothelial dysfunction represents a pathomechanism that is associated with most of these risk factors and stressors, and represents an early (subclinical) marker/predictor of atherosclerosis. Oxidative stress is a trigger of endothelial dysfunction and it is a hall-mark of cardiovascular diseases and of the risk factors/stressors that are responsible for their initiation. Endothelial function is largely based on endothelial nitric oxide synthase (eNOS) function and activity. Likewise, oxidative stress can lead to the loss of eNOS activity or even “uncoupling” of the enzyme by adverse regulation of well-defined “redox switches” in eNOS itself or up-/down-stream signaling molecules. Of note, not only eNOS function and activity in the endothelium are essential for vascular integrity and homeostasis, but also eNOS in perivascular adipose tissue plays an impo...
Aims CD40 ligand (CD40L) signaling controls vascular oxidative stress and related dysfunction in ... more Aims CD40 ligand (CD40L) signaling controls vascular oxidative stress and related dysfunction in angiotensin-II-induced arterial hypertension by regulating vascular immune cell recruitment and platelet activation. Here we investigated the role of CD40L in experimental hyperlipidemia. Methods and results Male wild type and CD40L−/− mice (C57BL/6 background) were subjected to high fat diet for sixteen weeks. Weight, cholesterol, HDL, and LDL levels, endothelial function (isometric tension recording), oxidative stress (NADPH oxidase expression, dihydroethidium fluorescence) and inflammatory parameters (inducible nitric oxide synthase, interleukin-6 expression) were assessed. CD40L expression, weight, leptin and lipids were increased, and endothelial dysfunction, oxidative stress and inflammation were more pronounced in wild type mice on a high fat diet, all of which was almost normalized by CD40L deficiency. Similar results were obtained in diabetic db/db mice with CD40/TRAF6 inhibitor...
Non-alcoholic steatohepatitis (NASH) is characterized by steatosis, panlobular inflammation, live... more Non-alcoholic steatohepatitis (NASH) is characterized by steatosis, panlobular inflammation, liver fibrosis and increased cardiovascular mortality. Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) are indirect glucagon like peptide 1 (GLP-1) agonists with antidiabetic and anti-inflammatory activity, used for the treatment of type 2 diabetes. Their potential and underlying mechanisms to treat metabolic liver inflammation and fibrosis as well as the associated vascular dysfunction remain to be explored. In the methionine/choline deficient (MCD) diet and Mdr2-/- models of NASH and liver fibrosis, treatment with sitagliptin and linagliptin significantly decreased parameters of steatosis and inflammation, which was accompanied by suppression of hepatic transcripts levels reflecting metabolic inflammation and fibrosis like SREBP-1c, FAS, TNFα, iNOS, α-SMA, Col1α1 and MMP-12. Moreover, gliptins reduced the number of liver infiltrating CD11b+Ly6Chi proinflammatory monocytes/macrophages ...
The European Cooperation in Science and Technology (COST) provides an ideal framework to establis... more The European Cooperation in Science and Technology (COST) provides an ideal framework to establish multi-disciplinary research networks. COST Action BM1203 (EU-ROS) represents a consortium of researchers from different disciplines who are dedicated to providing new insights and tools for better understanding redox biology and medicine and, in the long run, to finding new therapeutic strategies to target dysregulated redox processes in various diseases. This report highlights the major achievements of EU-ROS as well as research updates and new perspectives arising from its members. The EU-ROS consortium comprised more than 140 active members who worked together for four years on the topics briefly described below. The formation of reactive oxygen and nitrogen species (RONS) is an established hallmark of our aerobic environment and metabolism but RONS also act as messengers via redox regulation of essential cellular processes. The fact that many diseases have been found to be associat...
Epidemiological studies indicate that traffic noise increases the incidence of coronary artery di... more Epidemiological studies indicate that traffic noise increases the incidence of coronary artery disease, hypertension and stroke. The underlying mechanisms remain largely unknown. Field studies with nighttime noise exposure demonstrate that aircraft noise leads to vascular dysfunction, which is markedly improved by vitamin C, suggesting a key role of oxidative stress in causing this phenomenon. We developed a novel animal model to study the vascular consequences of aircraft noise exposure. Peak sound levels of 85 and mean sound level of 72 dBA applied by loudspeakers for 4 days caused an increase in systolic blood pressure, plasma noradrenaline and angiotensin II levels and induced endothelial dysfunction. Noise increased eNOS expression but reduced vascular NO levels because of eNOS uncoupling. Noise increased circulating levels of nitrotyrosine, interleukine-6 and vascular expression of the NADPH oxidase subunit Nox2, nitrotyrosine-positive proteins and of endothelin-1. FACS analys...
Objective. Oxidative stress and endothelial dysfunction contribute to pulmonary arterial hyperten... more Objective. Oxidative stress and endothelial dysfunction contribute to pulmonary arterial hypertension (PAH). The role of the nitrovasodilator pentaerythritol tetranitrate (PETN) on endothelial function and oxidative stress in PAH has not yet been defined. Methods and Results. PAH was induced by monocrotaline (MCT, i.v.) in Wistar rats. Low (30 mg/kg; MCT30), middle (40 mg/kg; MCT40), or high (60 mg/kg; MCT60) dose of MCT for 14, 28, and 42 d was used. MCT induced endothelial dysfunction, pulmonary vascular wall thickening, and fibrosis, as well as protein tyrosine nitration. Pulmonary arterial pressure and heart/body and lung/body weight ratio were increased in MCT40 rats (28 d) and reduced by oral PETN (10 mg/kg, 24 d) therapy. Oxidative stress in the vascular wall, in the heart, and in whole blood as well as vascular endothelin-1 signaling was increased in MCT40-treated rats and normalized by PETN therapy, likely by upregulation of heme oxygenase-1 (HO-1). PETN therapy improved en...
Excessive inflammation in sepsis causes microvascular thrombosis and thrombocytopenia associated ... more Excessive inflammation in sepsis causes microvascular thrombosis and thrombocytopenia associated with organ dysfunction and high mortality. The present studies aimed to investigate whether dipeptidyl peptidase-4 (DPP-4) inhibition and supplementation with glucagon-like peptide-1 (GLP-1) analogues improves endotoxaemia-associated microvascular thrombosis via immunomodulatory effects. Endotoxaemia was induced in C57BL/6 J mice by single injection of lipopolysaccharide (LPS) (17.5 for survival and 10 mg/kg for all other studies). For survival studies therapy was started 6 h after LPS injection. For all other studies drugs were administrated 48 h prior to LPS treatment. Endotoxaemic control mice showed severe thrombocytopenia, microvascular thrombosis in the pulmonary circulation (fluorescence imaging), increased lactate dehydrogenase (LDH)-activity, endothelial dysfunction and increased markers of inflammation in the aorta and whole blood (e.g. leukocyte-dependent oxidative burst, nitr...
Nitroglycerin (GTN) and other organic nitrates are widely used vasodilators. Their side effects a... more Nitroglycerin (GTN) and other organic nitrates are widely used vasodilators. Their side effects are development of nitrate tolerance and endothelial dysfunction. Given the potential of GTN to induce nitro-oxidative stress, we investigated the interaction between nitro-oxidative DNA damage and vascular dysfunction in experimental nitrate tolerance. Cultured endothelial hybridoma cells (EA.hy 926) and Wistar rats were treated with GTN (ex vivo: 10-1000 µM; in vivo: 10, 20 and 50 mg/kg/day for 3 days, s.c.). The level of DNA strand breaks, 8-oxoguanine and O (6)-methylguanine DNA adducts was determined by Comet assay, dot blot and immunohistochemistry. Vascular function was determined by isometric tension recording. DNA adducts and strand breaks were induced by GTN in cells in vitro in a concentration-dependent manner. GTN in vivo administration leads to endothelial dysfunction, nitrate tolerance, aortic and cardiac oxidative stress, formation of DNA adducts, stabilization of p53 and a...
Cardiovascular diseases are major contributors to global deaths and disability-adjusted life year... more Cardiovascular diseases are major contributors to global deaths and disability-adjusted life years, with hypertension as a significant risk factor for all cause death. The endothelium that lines the inner wall of the vasculature regulates essential haemostatic functions such as regulation of the vascular tone, circulation of blood cells, inflammation and platelet activity. Endothelial dysfunction is an early predictor of atherosclerosis and future cardiovascular events. We review the prognostic value of measurements of endothelial function, the clinical techniques for its determination, mechanisms leading to endothelial dysfunction and the therapeutic treatment of endothelial dysfunction. Since vascular oxidative stress and inflammation are major determinants of endothelial function, we also address current antioxidant and anti-inflammatory therapies. In light of recent data that speak against the prognostic value of endothelial function in healthy human cohorts, we also discuss alt...
Introduction: Sepsis is an inflammatory state. Proinflammatory enzymes like inducible-NO Synthase... more Introduction: Sepsis is an inflammatory state. Proinflammatory enzymes like inducible-NO Synthase (iNOS) and NADPH-Oxidase (NOX) are activated and influence endothelial function via oxidative and nitrosative stress. Inhibition of dipeptidyl-peptidase 4 (DPP4i) is a new approach to treat diabetic patients. Matubara et al. (Circulation, 2012) showed a positive influence of DPP4i on endothelial function in an animal model Hypothesis: DPP4 inhibition influences endothelial function, hemostasis and survival in a rodent model of septic shock Methods: C57/BL6j mice were pretreated with different DPP4i (linagliptin, sitagliptin) and GLP-1-analogue (GLP1a) liraglutide for 3 days. Aorta and heart tissue was used for western-blotting and rtPCR. Blood was examined for coagulation parameters (aPTT, PT), cell count and oxidative stress Results: Treatment with DPP4i and GLP1-a improved survival and blood pressure of septic animals significantly. LPS-induced oxidative stress and nitrosylated hemoglobin (Hb-NO) levels wer...
International journal of molecular sciences, Jan 5, 2015
Cardiovascular disease is a leading cause of death and reduced quality of life worldwide. Arteria... more Cardiovascular disease is a leading cause of death and reduced quality of life worldwide. Arterial vessels are a primary target for endothelial dysfunction and atherosclerosis, which is accompanied or even driven by increased oxidative stress. Recent research in this field identified different sources of reactive oxygen and nitrogen species contributing to the pathogenesis of endothelial dysfunction. According to lessons from the past, improvement of endothelial function and prevention of cardiovascular disease by systemic, unspecific, oral antioxidant therapy are obviously too simplistic an approach. Source- and cell organelle-specific antioxidants as well as activators of intrinsic antioxidant defense systems might be more promising. Since basic research demonstrated the contribution of different inflammatory cells to vascular oxidative stress and clinical trials identified chronic inflammatory disorders as risk factors for cardiovascular events, atherosclerosis and cardiovascular...
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Papers by Andreas Daiber