8 results on '"Schluter, KD"'
Search Results
2. P166 Extracellular RNA in cardiac ischemia/reperfusion injury: prevention of heart failure and cell damage by RNase1.
- Author
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Cabrera-Fuentes, H A, Ruiz-Meana, M, Kostin, S, Lecour, S, Hausenloy, DJ, Garcia-Dorado, DJ, Schluter, KD, and Preissner, KT
- Subjects
RNA ,REPERFUSION injury ,HEART failure ,RIBONUCLEASES ,MORTALITY ,MYOCARDIAL infarction - Abstract
Despite optimal therapy, the morbidity and mortality of patients presenting with an acute myocardial infarction (MI) remain significant. Extracellular RNA (eRNA), exposed after cell damage, serves as cofactor for coagulation proteases and cytokines thereby promoting their procoagulant and proinflammatory functions in vivo. Following myocardial ischemia/reperfusion (I/R) in mice or I/R induced in the isolated Langendorff heart, increased eRNA levels were found together with cell injury markers. Likewise, eRNA was released from cardiomyocytes under hypoxia and subsequently induced tumor-necrosis-factor-a (TNF-α) liberation by activation of TNF-α converting enzyme (TACE) and provoked cardiomyocyte death. Conversely, TNF-a promoted eRNA release especially under hypoxia, feeding a vicious cell damaging cycle during I/R. Administration of RNase1 or TAPI (TACE-inhibitor) prevented cell death and myocardial infarction. Likewise, RNase1 significantly reduced I/R-mediated energy exhaustion, opening of mitochondrial permeability transition pores (mPTP) as well as oxidative damage in cardiomyocytes. Together, RNase1 as well as inhibition of TACE provide novel therapeutic regimen to interfere with the adverse eRNA-TNF-a interplay and significantly reduce or prevent the pathological outcome of ischemic heart injury. [ABSTRACT FROM PUBLISHER]
- Published
- 2014
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3. Hypoxia-reoxygenation-induced endothelial barrier failure: role of RhoA, Rac1 and myosin light chain kinase.
- Author
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Aslam M, Schluter KD, Rohrbach S, Rafiq A, Nazli S, Piper HM, Noll T, Schulz R, and Gündüz D
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- Actins metabolism, Adherens Junctions metabolism, Animals, Antigens, CD metabolism, Aorta cytology, Aorta physiology, Cadherins metabolism, Calcium metabolism, Cell Hypoxia, Cyclic AMP analogs & derivatives, Cyclic AMP pharmacology, Guanine Nucleotide Exchange Factors antagonists & inhibitors, Guanine Nucleotide Exchange Factors metabolism, Human Umbilical Vein Endothelial Cells, Humans, In Vitro Techniques, Permeability, Rats, Signal Transduction, Stress Fibers metabolism, Swine, Vasoconstriction, rho-Associated Kinases metabolism, Endothelial Cells metabolism, Muscle, Smooth, Vascular physiology, Myosin-Light-Chain Kinase metabolism, rac1 GTP-Binding Protein metabolism, rhoA GTP-Binding Protein metabolism
- Abstract
Hypoxia-reoxygenation induces loss of endothelial barrier function and oedema formation, which presents a major impediment for recovery of the organ. The integrity of the endothelial barrier is highly dependent on its contractile machinery and actin dynamics, which are precisely regulated by Rho GTPases. Perturbed activities of these Rho-GTPases under hypoxia-reoxygenation lead to derangement of the actin cytoskeleton and therefore may affect the integrity of the endothelial barrier. The aim of the present study was to analyse the role of these GTPases in regulating endothelial barrier function during hypoxia-reoxygenation in cultured porcine aortic endothelial cells and isolated perfused rat hearts. Hypoxia-reoxygenation induced an increase in albumin permeability of endothelial monolayers accompanied by an activation of the endothelial contractile machinery, derangement of the actin cytoskeleton and loss of VE-cadherin from cellular junctions. Inhibition of contractile activation with ML-7 partially protected against hypoxia-reoxygenation-induced hyperpermeability. Likewise, reoxygenation caused an increase in RhoA and a reduction in Rac1 activity accompanied by enhanced stress fibre formation and loss of peripheral actin. Inhibition of RhoA/rho kinase (Rock) signalling with RhoA or Rock inhibitors led to a complete depolymerisation and derangement of the actin cytoskeleton and worsened hypoxia-reoxygenation-induced hyperpermeability. Activation of Rac1 using a cAMP analogue, 8-CPT-O-Me-cAMP, which specifically activates Epac/Rap1 signalling, restored peripheral localisation of actin and VE-cadherin at cellular junctions and abrogated reoxygenation-induced hyperpermeability. Similar results were reproduced in isolated saline-perfused rat hearts. These data show that activation of Rac1 but not the inhibition of RhoA preserves endothelial integrity against reoxygenation-induced loss of barrier function.
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- 2013
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4. Decorin deficiency in diabetic mice: aggravation of nephropathy due to overexpression of profibrotic factors, enhanced apoptosis and mononuclear cell infiltration.
- Author
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Merline R, Lazaroski S, Babelova A, Tsalastra-Greul W, Pfeilschifter J, Schluter KD, Gunther A, Iozzo RV, Schaefer RM, and Schaefer L
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- Animals, Blotting, Northern, Blotting, Western, Cells, Cultured, Connective Tissue Growth Factor metabolism, Cyclin-Dependent Kinase Inhibitor p27 biosynthesis, Decorin, Diabetes Mellitus genetics, Epithelial Cells metabolism, Extracellular Matrix metabolism, Extracellular Matrix Proteins genetics, Fibrosis metabolism, Humans, Kidney metabolism, Mice, Mice, Knockout, Neutrophil Infiltration physiology, Podocytes metabolism, Polysaccharides metabolism, Proteinuria metabolism, Proteoglycans genetics, Receptor, IGF Type 1 metabolism, Transforming Growth Factor beta1 metabolism, Apoptosis physiology, Diabetes Mellitus metabolism, Diabetic Neuropathies metabolism, Diabetic Neuropathies pathology, Extracellular Matrix Proteins deficiency, Monocytes physiology, Proteoglycans deficiency
- Abstract
Although deficiency of the small leucine-rich proteoglycan decorin aggravates diabetic nephropathy in mice, the precise mechanisms of action are not fully understood. In the present study we used decorin-deficient mice (Dcn(-/-)) to further elucidate the molecular mechanisms involved in the protective action of decorin in diabetes. We discovered that streptozotocin-induced diabetes in Dcn(-/-) mice led to increased proteinuria associated with enhanced cyclin-dependent kinase inhibitor p27Kip1 in podocytes and tubular epithelial cells. Furthermore, lack of decorin increased the rate of apoptosis and caused overexpression of the IGF-IR in tubular epithelial cells of diabetic kidneys. In vitro experiments using human proximal renal epithelial cells showed that recombinant decorin was bound to the IGF-IR and protected against high glucose-mediated apoptosis. Furthermore, overexpression of TGFbeta1 and CTGF triggered by decorin deficiency resulted in enhanced accumulation of extracellular matrix in diabetic kidneys. Notably, diabetic Dcn(-/-) kidneys revealed marked upregulation of the proinflammatory proteoglycan biglycan and enhanced infiltration of mononuclear cells. Collectively, our results indicate that decorin is a protective agent during the development of diabetic nephropathy. Future therapeutic approaches that would either enhance the endogenous production of decorin or deliver recombinant decorin to the diseased kidney might improve the outcome of patients with diabetic nephropathy.
- Published
- 2009
5. Parathyroid hormone-related protein (PTHrP)-dependent regulation of bcl-2 and tissue inhibitor of metalloproteinase (TIMP)-1 in coronary endothelial cells.
- Author
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Conzelmann C, Krasteva G, Weber K, Kummer W, and Schluter KD
- Subjects
- Animals, Apoptosis, Cells, Cultured, Down-Regulation, Male, Parathyroid Hormone-Related Protein genetics, Phenylephrine pharmacology, Proto-Oncogene Proteins c-bcl-2 genetics, RNA, Antisense metabolism, Rats, Rats, Wistar, Tissue Inhibitor of Metalloproteinase-1 genetics, Tissue Inhibitor of Metalloproteinase-2 genetics, Tissue Inhibitor of Metalloproteinase-2 metabolism, Transforming Growth Factor beta1 pharmacology, bcl-2-Associated X Protein genetics, bcl-2-Associated X Protein metabolism, Coronary Vessels cytology, Endothelial Cells metabolism, Endothelium, Vascular cytology, Parathyroid Hormone-Related Protein metabolism, Proto-Oncogene Proteins c-bcl-2 metabolism, Tissue Inhibitor of Metalloproteinase-1 metabolism
- Abstract
Background: An increased susceptibility of micro-vascular endothelial cells to apoptosis is considered to be an initial event leading to atherosclerosis. Parathyroid hormone-related peptide (PTHrP) is known to protect endothelial cells against apoptosis by the regulation of the anti-apoptotic gene bcl-2. As tissue inhibitor of metalloproteinase (TIMP-1) expression is regulated by bcl-2, we hypothesized that endothelial expression of PTHrP also regulates the expression of TIMP-1., Methods: The steady state mRNA expressions of bcl-2, bax, TIMP-1, and TIMP-2 were analyzed by real-time RT-PCR and their protein expression by immunoblotting. The tissue distribution of PTHrP was investigated in cryosections of hearts from normotensive and hypertensive rats., Results: Phenylephrine, an alpha(1)-adrenoceptor agonist, increased the expression of PTHrP, bcl-2, and TIMP-1. Transfection of endothelial cells with oligonucleotides directed against PTHrP attenuated this effect. Antisense transfection and TGF-beta(1) (10 ng/ml) decreased the expression of PTHrP, bcl-2, TIMP-1, and TIMP-2, but not that of bax. Endothelial cells were identified as the main source of PTHrP in the heart. Endothelial cells in hearts from spontaneously hypertensive rats showed reduced staining with a PTHrP antibody compared to control normotensive hearts., Conclusions: These data suggests that the down-regulation of PTHrP favours atherosclerosis in chronic pressure overload., (2009 S. Karger AG, Basel.)
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- 2009
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6. Impaired release of bioactive parathyroid hormone-related peptide in patients with pulmonary hypertension and endothelial dysfunction.
- Author
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Sokolova J, Zimmermann R, Kreuder J, Michel-Behnke I, Schranz D, Piper HM, and Schluter KD
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- Acetylcholine pharmacology, Adolescent, Blood Pressure, Child, Child, Preschool, Endothelium, Vascular drug effects, Endothelium, Vascular physiopathology, Female, Femoral Artery drug effects, Femoral Artery physiopathology, Humans, Hypertension, Pulmonary physiopathology, Iloprost pharmacology, Infant, Infant, Newborn, Male, Oxygen pharmacology, Pulmonary Artery drug effects, Pulmonary Artery physiopathology, Vasodilator Agents pharmacology, Endothelium, Vascular metabolism, Femoral Artery metabolism, Hypertension, Pulmonary metabolism, Mechanotransduction, Cellular, Parathyroid Hormone-Related Protein blood, Pulmonary Artery metabolism
- Abstract
Background: Parathyroid hormone-related protein (PTHrP) is an endothelial-derived vasoactive peptide. This study investigated whether bioactive PTHrP is locally released in a pressure-dependent way., Methods: A PTHrP antibody directed against the midregional part of PTHrP was used to analyze PTHrP in plasma samples. The biological activity of this PTHrP-like peptide was investigated in vitro. Plasma values were determined in samples from the left pulmonary artery and the arteria femoralis, taken under basal conditions and after the application of oxygen or iloprost to lower the pulmonary pressure. Twenty young patients (mean age 6.5 years), who were catheterized for an analysis of the reactivity of the pulmonary bed, were investigated. Endothelial function was investigated by acetylcholine responsiveness., Results: The antibody recognized a 30-kDa protein with in vitro PTHrP-like activity. In 11 patients (responders) with intact endothelial function, the PTHrP values determined in the left pulmonary artery were higher than those in the arteria femoralis. The local increase in the PTHrP concentration was reduced when either oxygen or iloprost lowered the pressure. Nine patients with endothelial dysfunction did not show any concentration gradients at any time (nonresponders)., Conclusions: The local concentration of bioactive PTHrP is increased in patients with pulmonary hypertension and normal endothelial function., (Copyright (c) 2007 S. Karger AG, Basel.)
- Published
- 2007
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7. Tuberoinfundibular peptide of 39 residues: a new mediator of cardiac function via nitric oxide production in the rat heart.
- Author
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Ross G, Engel P, Abdallah Y, Kummer W, and Schluter KD
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- Animals, Aorta drug effects, Cells, Cultured, Coronary Vessels drug effects, Cyclic GMP analysis, Depression, Chemical, Enzyme Inhibitors pharmacology, Gene Expression, Heart Ventricles drug effects, Male, Myocardial Contraction drug effects, Neuropeptides genetics, Neuropeptides pharmacology, Nitric Oxide antagonists & inhibitors, Nitric Oxide Donors pharmacology, Nitric Oxide Synthase antagonists & inhibitors, Nitroarginine pharmacology, Pressure, Rats, Rats, Wistar, Receptor, Parathyroid Hormone, Type 2 antagonists & inhibitors, Receptor, Parathyroid Hormone, Type 2 physiology, Reverse Transcriptase Polymerase Chain Reaction, Vasodilation drug effects, Heart physiology, Neuropeptides physiology, Nitric Oxide biosynthesis
- Abstract
Tuberoinfundibular peptide (TIP39) was initially identified as a neurotransmitter and agonist of the PTH2 receptor, which is expressed in the cardiovascular system. This study documents for the first time the cardiac expression and function of TIP39. Expression was analyzed via RT-PCR. Function was characterized on Langendorff-perfused rat hearts as left ventricular developed pressure (LVDP) and on isolated cells via a cell edge detection system. cGMP levels were detected with RIA. Tuberoinfundibular peptide (TIP39) mRNA was found to be constitutively expressed in coronary endothelium cells, isolated cardiomyocytes, ventricles, atria, and aorta. At first we investigated the vasodilatory properties of TIP39 (100 nM) in the presence of L-nitro-arginine (L-NA, 100 microM). Surprisingly, TIP39 had no vasodilatory effect but decreased LVDP by 35 +/- 7%. In the absence of L-NA, addition of TIP39 decreased LVDP by 8 +/- 2%. The PTH2 receptor antagonist Trp23-Tyr36-PTHrP (1-36, 100 nM) abolished this TIP39 effect in the presence of L-NA. The experiments with isolated cardiomyocytes provided similar results. TIP39 (10 nM) lowered the contraction amplitude by 6 +/- 3%. In the presence of L-NA (100 micromol/liter), TIP39 lowered the amplitude by 34 +/- 6%. cGMP concentration in cardiomyocytes was stimulated by TIP39 (10 nM) in the same range as by the nitric oxide (NO) donor SNAP (100 microM). In the presence of L-NA, this increase was abolished. These results suggest that an inhibition of endogenous NO production unmasks a profound negative inotropic effect of TIP39 that is mediated by an activation of the PTH2 receptor. The results obtained with isolated cardiomyocytes suggest that myocyte-derived NO, rather than vascular NO, is responsible for this effect. cGMP seems to be the downstream signal of produced NO.
- Published
- 2005
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8. Parathyroid hormone-related peptide improves contractile function of stunned myocardium in rats and pigs.
- Author
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Jansen J, Gres P, Umschlag C, Heinzel FR, Degenhardt H, Schluter KD, Heusch G, and Schulz R
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- Animals, Coronary Circulation drug effects, Heart physiopathology, Hemodynamics drug effects, In Vitro Techniques, Myocardial Stunning, Myocardium metabolism, Myocytes, Cardiac drug effects, Myocytes, Cardiac physiology, Oxygen Consumption drug effects, Parathyroid Hormone-Related Protein, Peptide Hormones physiology, Rats, Rats, Wistar, Swine, Swine, Miniature, Vascular Resistance drug effects, Ventricular Function drug effects, Heart drug effects, Myocardial Contraction drug effects, Parathyroid Hormone pharmacology, Peptide Fragments pharmacology
- Abstract
The effect of synthetic parathyroid hormone (PTH)-related peptide [PTHrP(1-34)] on regional myocardial function was studied in 11 anesthetized pigs. Intracoronary infusion of PTHrP (cumulative dose: 14 +/- 1 microg) decreased coronary resistance to 33 +/- 2% of baseline (P < 0.05) and regional myocardial function to 90 +/- 3% of baseline (not significant). Ischemia-reperfusion alters the activity of several kinases and therefore possibly the myocardial effects of PTHrP. In stunned myocardium, induced by 20-min ischemia and 30-min reperfusion, the dose of PTHrP reducing coronary resistance to a minimum of 29 +/- 2% was decreased to 8 +/- 2 microg (P < 0.05). Regional myocardial function was no longer decreased but increased to 132 +/- 9% (P < 0.05). The increase in regional myocardial function during PTHrP was inversely related to baseline function at 30-min reperfusion in vivo (r = 0.9) as well as in myocytes isolated from stunned pig hearts (r = 0.7). In isolated rat hearts subjected to 30-min global ischemia followed by 30-min reperfusion, blockade of endogenous PTHrP by d-Trp(12)-Tyr(34)-PTH(7-34) attenuated the recovery of left ventricular developed pressure by 30 +/- 14% (P < 0.05). Thus endogenous and exogenous PTHrP impact on the function of stunned myocardium.
- Published
- 2003
- Full Text
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