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Norbert Weissmann - One of the best experts on this subject based on the ideXlab platform.
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chronic intratracheal application of the soluble guanylyl cyclase stimulator bay 41 8543 ameliorates Experimental Pulmonary Hypertension
Oncotarget, 2017Co-Authors: Matthieu Amirjanians, Akylbek Sydykov, Johannespeter Stasch, Baktybek Kojonazarov, Ralf P Brandes, Bakytbek Egemnazarov, Himal Luitel, Kabita Pradhan, Gorden Redlich, Norbert WeissmannAbstract:// Matthieu Amirjanians 1 , Bakytbek Egemnazarov 1 , Akylbek Sydykov 1 , Baktybek Kojonazarov 1 , Ralf Brandes 3 , Himal Luitel 1 , Kabita Pradhan 1 , Johannes-Peter Stasch 4,5 , Gorden Redlich 6 , Norbert Weissmann 1 , Friedrich Grimminger 1 , Werner Seeger 1,2 , Hossein Ghofrani 1 and Ralph Schermuly 1,2 1 University of Giessen Lung Center, Giessen, Germany 2 Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany 3 Institute for Cardiovascular Physiology, J.W. Goethe University, Frankfurt, Germany 4 Cardiology Research, Pharmaceuticals, Bayer AG, Wuppertal, Germany 5 Institute of Pharmacy, Martin Luther University of Halle Wittenberg, Halle, Germany 6 Research Pharmacokinetics, Pharmaceuticals, Bayer AG, Wuppertal, Germany Correspondence to: Ralph Schermuly, email: // Keywords : monocrotaline; cGMP; nitric oxide; Pulmonary Hypertension; remodelling; Pathology Section Received : August 19, 2016 Accepted : March 08, 2017 Published : March 31, 2017 Abstract Dysfunction of the NO/sGC/cGMP signaling pathway has been implicated in the pathogenesis of Pulmonary Hypertension (PH). Therefore, agents stimulating cGMP synthesis via sGC are important therapeutic options for treatment of PH patients. An unwanted effect of this novel class of drugs is their systemic hypotensive effect. We tested the hypothesis that aerosolized intra-tracheal delivery of the sGC stimulator BAY41-8543 could diminish its systemic vasodilating effect. Pharmacodynamics and -kinetics of BAY41-8543 after single intra-tracheal delivery was tested in healthy rats. Four weeks after a single injection of monocrotaline (MCT, 60 mg/kg s.c.), rats were randomized to a two-week treatment with either placebo, BAY 41-8543 (10 mg/kg per os (PO)) or intra-tracheal (IT) instillation (3 mg/kg or 1 mg/kg). Circulating concentrations of the drug 10 mg/kg PO and 3 mg/kg IT were comparable. BAY 41-8543 was detected in the lung tissue and broncho-alveolar fluid after IT delivery at higher concentrations than after PO administration. Systemic arterial pressure transiently decreased after oral BAY 41-8543 and was unaffected by intratracheal instillation of the drug. PO 10 mg/kg and IT 3 mg/kg regimens partially reversed Pulmonary Hypertension and improved heart function in MCT-injected rats. Minor efficacy was noted in rats treated IT with 1 mg/kg. The degree of Pulmonary vascular remodeling was largely reversed in all treatment groups. Intratracheal administration of BAY 41-8543 reverses PAH and vascular structural remodeling in MCT-treated rats. Local lung delivery is not associated with systemic blood pressure lowering and represents thus a further development of PH treatment with sGC stimulators.
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inhibition of microrna 17 improves lung and heart function in Experimental Pulmonary Hypertension
American Journal of Respiratory and Critical Care Medicine, 2012Co-Authors: Soni Savai Pullamsetti, Norbert Weissmann, Bhola K Dahal, Rajkumar Savai, Hossein Ardeschir Ghofrani, Friedrich Grimminger, Baktybek Kojonazarov, Carmen Doebele, Ariane Fischer, Angelika BonauerAbstract:Rationale: MicroRNAs (miRs) control various cellular processes in tissue homeostasis and disease by regulating gene expression on the posttranscriptional level. Recently, it was demonstrated that the expression of miR-21 and members of the miR-17–92 cluster was significantly altered in Experimental Pulmonary Hypertension (PH).Objectives: To evaluate the therapeutic efficacy and antiremodeling potential of miR inhibitors in the pathogenesis of PH.Methods: We first tested the effects of miR inhibitors (antagomirs), which were specifically designed to block miR-17 (A-17), miR-21 (A-21), and miR-92a (A-92a) in chronic hypoxia-induced PH in mice and A-17 in monocrotaline-induced PH in rats. Moreover, biological function of miR-17 was analyzed in cultured Pulmonary artery smooth muscle cells.Measurements and Main Results: In the PH mouse model, A-17 and A-21 reduced right ventricular systolic pressure, and all antagomirs decreased Pulmonary arterial muscularization. However, only A-17 reduced hypoxia-induced ri...
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inhibition of microrna 17 improves lung and heart function in Experimental Pulmonary Hypertension
American Thoracic Society International Conference, 2012Co-Authors: Soni Savai Pullamsetti, Norbert Weissmann, Bhola K Dahal, Rajkumar Savai, Hossein Ardeschir Ghofrani, Friedrich Grimminger, Baktybek Kojonazarov, Carmen Doebele, Ariane Fischer, Angelika BonauerAbstract:MicroRNAs (miRs) control various cellular processes in tissue homeostasis and disease by regulating gene expression on the posttranscriptional level. Recently, it was demonstrated that the expression of miR-21 and members of the miR-17-92 cluster was significantly altered in Experimental Hypertension (PH). We evaluated whether inhibition of these miRs may provide a novel therapeutic option. We first tested the effects of miR inhibitors (antagomirs), which were specifically designed to block miR-17 (A-17), -21 (A-21) and -92a (A-92a) in chronic hypoxia-induced PH in mice. A-17 and A-21 reduced right ventricular systolic pressure (RVSP) and all antagomirs decreased Pulmonary arterial muscularization. However, only A-17 reduced hypoxia-induced right ventricular hypertrophy and improved Pulmonary artery acceleration time (PAAT). Therefore, we additionally tested the effects of A-17 in monocrotaline-induced PH in rats. A-17 treatment significantly decreased RVSP and total Pulmonary vascular resistance index, increased PAAT, normalized cardiac output and decreased Pulmonary vascular remodelling. Among the tested miR-17 targets, the cyclin-dependent kinase inhibitor 1A (p21) was upregulated in lungs undergoing A-17 treatment. Likewise, in human Pulmonary artery smooth muscle cells, A-17 increased p21. Overexpression of miR-17 significantly reduced p21 expression and increased proliferation of smooth muscle cells. Our data demonstrate that A-17 improves heart and lung function in Experimental PH by interfering with lung vascular and right ventricular remodeling. Thus, inhibition of miR-17 may represent a novel therapeutic concept to ameliorate disease state in PH.
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effects of riociguat in severe Experimental Pulmonary Hypertension
European Respiratory Journal, 2011Co-Authors: Baktybek Kojonazarov, Norbert Weissmann, Johannespeter Stasch, Ralph T. Schermuly, Hossein Ardeschir Ghofrani, Friedrich Grimminger, Werner Seeger, Michaela LangAbstract:Introduction: The NO-sGC-cGMP signaling pathway is impaired in different cardiovascular diseases, including Pulmonary Hypertension (PH). Riociguat is the first of a new class of drugs, the sGC stimulators. Riociguat has a dual mode of action: it sensitizes sGC to the body's own NO and can also increase sGC activity in the absence of NO, causing vasorelaxation, anti-proliferation and anti-fibrotic effects. Aim: The aim of the study was to investigate the effects of riociguat as compared to the PDE5 inhibitor sildenafil on Pulmonary vascular remodeling in severe Experimental PH. Methods: Angioproliferative PH was induced in rats by combined exposure to the VEGFr antagonist SU5416 and hypoxia. 21 days thereafter, rats were randomized for treatment with riociguat (10 mg/kg), sildenafil (50 mg/kg) or vehicle for the next 14 days. Echocardiography and invasive hemodynamic measurements were performed. Pulmonary vascular remodeling was assessed by histomorphomety. Results: In rats with established PH, RVSP was significantly decreased by treatment with riociguat to 73±4 mmHg (p<0.01) and sildenafil to 80±3 mmHg (p<0.05) as compared to placebo (89±3 mmHg). No significant difference in systemic arterial pressure was detected between placebo and treated animals. Both compounds significantly decreased RV hypertrophy and improved RV function by normalization of TAPSE and Tei index, but effects of riociguat were more pronounced. Riociguat significantly reduced the proportion of occluded arteries, increased proportion of opened arteries and decreased neointima/media ratio. Conclusion: We demonstrated that riociguat effectively suppresses Pulmonary vascular remodeling and significantly improves RV function in an Experimental model of PH.
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effects of riociguat in severe Experimental Pulmonary Hypertension
BMC Pharmacology, 2011Co-Authors: Baktybek Kojonazarov, Norbert Weissmann, Johannespeter Stasch, Ralph T. Schermuly, Hossein Ardeschir Ghofrani, Friedrich Grimminger, Werner Seeger, Michaela LangAbstract:The NO-sGC-cGMP signaling pathway is impaired in different cardiovascular diseases, including Pulmonary Hypertension (PH). Riociguat is the first of a new class of drugs, the soluble guanylate cyclase stimulators. Riociguat has a dual mode of action: it sensitizes sGC to the body’s own NO and can also increase sGC activity in the absence of NO, causing vasorelaxation, anti-proliferation and anti-fibrotic effects. The aim of the study was to investigate the effects of riociguat as compared to the PDE5 inhibitor sildenafil on Pulmonary vascular remodeling in severe Experimental PH.
Ralph T. Schermuly - One of the best experts on this subject based on the ideXlab platform.
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sildenafil potentiates bone morphogenetic protein signaling in Pulmonary arterial smooth muscle cells and in Experimental Pulmonary Hypertension
Arteriosclerosis Thrombosis and Vascular Biology, 2013Co-Authors: Jun Yang, Ralph T. Schermuly, Rafia S Allamki, Astrid Weiss, Joachim Berk, Nicholas W MorrellAbstract:Objective— Mutations in the bone morphogenetic protein type II receptor (BMPR-II) are responsible for the majority of cases of heritable Pulmonary arterial Hypertension (PAH), and BMPR-II deficiency contributes to idiopathic and Experimental forms of PAH. Sildenafil, a potent type-5 nucleotide-dependent phosphodiesterase inhibitor, is an established treatment for PAH, but whether sildenafil affects bone morphogenetic protein (BMP) signaling in the Pulmonary circulation remains unknown. Methods and Results— Studies were undertaken in human Pulmonary arterial smooth muscle cells (PASMCs) and in vivo in the monocrotaline rat model of PAH. In PASMCs, sildenafil enhanced BMP4-induced phosphorylation of Smad1/5, Smad nuclear localization, and Inhibitor of DNA binding protein 1 gene and protein expression. This effect was mimicked by 8-bromo-cyclic GMP. Pharmacological inhibition or small interfering RNA knockdown of cyclic GMP-dependent protein kinase I inhibited the effect of sildenafil on BMP signaling. In functional studies, we observed that sildenafil potentiated the antiproliferative effects of BMP4 on PASMC proliferation. Furthermore, sildenafil restored the antiproliferative response to BMP4 in PASMCs harboring mutations in BMPR-II. In the monocrotaline rat model of PAH, which is characterized by BMPR-II deficiency, sildenafil prevented the development of Pulmonary Hypertension and vascular remodeling, and partly restored Smad1/5 phosphorylation and Inhibitor of DNA binding protein 1 gene expression in vivo in monocrotaline exposed rat lungs. Conclusion— Sildenafil enhances canonical BMP signaling via cyclic GMP and cyclic GMP-dependent protein kinase I in vitro and in vivo, and partly restores deficient BMP signaling in BMPR-II mutant PASMCs. Our findings demonstrate a novel mechanism of action of sildenafil in the treatment of PAH and suggest that targeting BMP signaling may be beneficial in this disease.
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par 2 inhibition reverses Experimental Pulmonary Hypertension
Circulation Research, 2012Co-Authors: Grazyna Kwapiszewska, Bhola K Dahal, Ralph T. Schermuly, Hossein Ardeschir Ghofrani, Baktybek Kojonazarov, Philipp Markart, Leigh M Marsh, Christian Taube, Andreas Meinhardt, Martin SteinhoffAbstract:Rationale: A hallmark of the vascular remodeling process underlying Pulmonary Hypertension (PH) is the aberrant proliferation and migration of Pulmonary arterial smooth muscle cells (PASMC). Accumulating evidence suggests that mast cell mediators play a role in the pathogenesis of PH. Objective: In the present study we investigated the importance of protease-activated receptor (PAR)–2 and its ligand mast cell tryptase in the development of PH. Methods and Results: Our results revealed strong increase in PAR-2 and tryptase expression in the lungs of idiopathic Pulmonary arterial Hypertension (IPAH) patients, hypoxia-exposed mice, and monocrotaline (MCT)–treated rats. Elevated tryptase levels were also detected in plasma samples from IPAH patients. Hypoxia and platelet-derived growth factor (PDGF)–BB upregulated PAR-2 expression in PASMC. This effect was reversed by HIF (hypoxia inducible factor)–1α depletion, PDGF-BB neutralizing antibody, or the PDGF-BB receptor antagonist Imatinib. Attenuation of PAR-2 expression was also observed in smooth muscle cells of Pulmonary vessels of mice exposed to hypoxia and rats challenged with MCT in response to Imatinib treatment. Tryptase induced PASMC proliferation and migration as well as enhanced synthesis of fibronectin and matrix metalloproteinase-2 in a PAR-2- and ERK1/2-dependent manner, suggesting that PAR-2-dependent signaling contributes to vascular remodeling by various mechanisms. Furthermore, PAR-2 −/− mice were protected against hypoxia-induced PH, and PAR-2 antagonist application reversed established PH in the hypoxia mouse model. Conclusions: Our study identified a novel role of PAR-2 in vascular remodeling in the lung. Interference with this pathway may offer novel therapeutic options for the treatment of PH.
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effects of riociguat in severe Experimental Pulmonary Hypertension
European Respiratory Journal, 2011Co-Authors: Baktybek Kojonazarov, Norbert Weissmann, Johannespeter Stasch, Ralph T. Schermuly, Hossein Ardeschir Ghofrani, Friedrich Grimminger, Werner Seeger, Michaela LangAbstract:Introduction: The NO-sGC-cGMP signaling pathway is impaired in different cardiovascular diseases, including Pulmonary Hypertension (PH). Riociguat is the first of a new class of drugs, the sGC stimulators. Riociguat has a dual mode of action: it sensitizes sGC to the body's own NO and can also increase sGC activity in the absence of NO, causing vasorelaxation, anti-proliferation and anti-fibrotic effects. Aim: The aim of the study was to investigate the effects of riociguat as compared to the PDE5 inhibitor sildenafil on Pulmonary vascular remodeling in severe Experimental PH. Methods: Angioproliferative PH was induced in rats by combined exposure to the VEGFr antagonist SU5416 and hypoxia. 21 days thereafter, rats were randomized for treatment with riociguat (10 mg/kg), sildenafil (50 mg/kg) or vehicle for the next 14 days. Echocardiography and invasive hemodynamic measurements were performed. Pulmonary vascular remodeling was assessed by histomorphomety. Results: In rats with established PH, RVSP was significantly decreased by treatment with riociguat to 73±4 mmHg (p<0.01) and sildenafil to 80±3 mmHg (p<0.05) as compared to placebo (89±3 mmHg). No significant difference in systemic arterial pressure was detected between placebo and treated animals. Both compounds significantly decreased RV hypertrophy and improved RV function by normalization of TAPSE and Tei index, but effects of riociguat were more pronounced. Riociguat significantly reduced the proportion of occluded arteries, increased proportion of opened arteries and decreased neointima/media ratio. Conclusion: We demonstrated that riociguat effectively suppresses Pulmonary vascular remodeling and significantly improves RV function in an Experimental model of PH.
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effects of riociguat in severe Experimental Pulmonary Hypertension
BMC Pharmacology, 2011Co-Authors: Baktybek Kojonazarov, Norbert Weissmann, Johannespeter Stasch, Ralph T. Schermuly, Hossein Ardeschir Ghofrani, Friedrich Grimminger, Werner Seeger, Michaela LangAbstract:The NO-sGC-cGMP signaling pathway is impaired in different cardiovascular diseases, including Pulmonary Hypertension (PH). Riociguat is the first of a new class of drugs, the soluble guanylate cyclase stimulators. Riociguat has a dual mode of action: it sensitizes sGC to the body’s own NO and can also increase sGC activity in the absence of NO, causing vasorelaxation, anti-proliferation and anti-fibrotic effects. The aim of the study was to investigate the effects of riociguat as compared to the PDE5 inhibitor sildenafil on Pulmonary vascular remodeling in severe Experimental PH.
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combined tyrosine and serine threonine kinase inhibition by sorafenib prevents progression of Experimental Pulmonary Hypertension and myocardial remodeling
Circulation, 2008Co-Authors: Martina Klein, Norbert Weissmann, Soni Savai Pullamsetti, Ralph T. Schermuly, Eva Dony, Peter Ellinghaus, Hendrik Milting, Bernd Riedl, Sevdalina Nikolova, Rajkumar SavaiAbstract:Background— Inhibition of tyrosine kinases, including platelet-derived growth factor receptor, can reduce Pulmonary arterial pressure in Experimental and clinical Pulmonary Hypertension. We hypothesized that inhibition of the serine/threonine kinases Raf-1 (also termed c-Raf) and b-Raf in addition to inhibition of tyrosine kinases effectively controls Pulmonary vascular and right heart remodeling in Pulmonary Hypertension. Methods and Results— We investigated the effects of the novel multikinase inhibitor sorafenib, which inhibits tyrosine kinases as well as serine/threonine kinases, in comparison to imatinib, a tyrosine kinase inhibitor, on hemodynamics, Pulmonary and right ventricular (RV) remodeling, and downstream signaling in Experimental Pulmonary Hypertension. Fourteen days after monocrotaline injection, male rats were treated orally for another 14 days with sorafenib (10 mg/kg per day), imatinib (50 mg/kg per day), or vehicle (n=12 to 16 per group). RV systolic pressure was decreased to 35.0±1.5 m...
Friedrich Grimminger - One of the best experts on this subject based on the ideXlab platform.
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inhibition of microrna 17 improves lung and heart function in Experimental Pulmonary Hypertension
American Journal of Respiratory and Critical Care Medicine, 2012Co-Authors: Soni Savai Pullamsetti, Norbert Weissmann, Bhola K Dahal, Rajkumar Savai, Hossein Ardeschir Ghofrani, Friedrich Grimminger, Baktybek Kojonazarov, Carmen Doebele, Ariane Fischer, Angelika BonauerAbstract:Rationale: MicroRNAs (miRs) control various cellular processes in tissue homeostasis and disease by regulating gene expression on the posttranscriptional level. Recently, it was demonstrated that the expression of miR-21 and members of the miR-17–92 cluster was significantly altered in Experimental Pulmonary Hypertension (PH).Objectives: To evaluate the therapeutic efficacy and antiremodeling potential of miR inhibitors in the pathogenesis of PH.Methods: We first tested the effects of miR inhibitors (antagomirs), which were specifically designed to block miR-17 (A-17), miR-21 (A-21), and miR-92a (A-92a) in chronic hypoxia-induced PH in mice and A-17 in monocrotaline-induced PH in rats. Moreover, biological function of miR-17 was analyzed in cultured Pulmonary artery smooth muscle cells.Measurements and Main Results: In the PH mouse model, A-17 and A-21 reduced right ventricular systolic pressure, and all antagomirs decreased Pulmonary arterial muscularization. However, only A-17 reduced hypoxia-induced ri...
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inhibition of microrna 17 improves lung and heart function in Experimental Pulmonary Hypertension
American Thoracic Society International Conference, 2012Co-Authors: Soni Savai Pullamsetti, Norbert Weissmann, Bhola K Dahal, Rajkumar Savai, Hossein Ardeschir Ghofrani, Friedrich Grimminger, Baktybek Kojonazarov, Carmen Doebele, Ariane Fischer, Angelika BonauerAbstract:MicroRNAs (miRs) control various cellular processes in tissue homeostasis and disease by regulating gene expression on the posttranscriptional level. Recently, it was demonstrated that the expression of miR-21 and members of the miR-17-92 cluster was significantly altered in Experimental Hypertension (PH). We evaluated whether inhibition of these miRs may provide a novel therapeutic option. We first tested the effects of miR inhibitors (antagomirs), which were specifically designed to block miR-17 (A-17), -21 (A-21) and -92a (A-92a) in chronic hypoxia-induced PH in mice. A-17 and A-21 reduced right ventricular systolic pressure (RVSP) and all antagomirs decreased Pulmonary arterial muscularization. However, only A-17 reduced hypoxia-induced right ventricular hypertrophy and improved Pulmonary artery acceleration time (PAAT). Therefore, we additionally tested the effects of A-17 in monocrotaline-induced PH in rats. A-17 treatment significantly decreased RVSP and total Pulmonary vascular resistance index, increased PAAT, normalized cardiac output and decreased Pulmonary vascular remodelling. Among the tested miR-17 targets, the cyclin-dependent kinase inhibitor 1A (p21) was upregulated in lungs undergoing A-17 treatment. Likewise, in human Pulmonary artery smooth muscle cells, A-17 increased p21. Overexpression of miR-17 significantly reduced p21 expression and increased proliferation of smooth muscle cells. Our data demonstrate that A-17 improves heart and lung function in Experimental PH by interfering with lung vascular and right ventricular remodeling. Thus, inhibition of miR-17 may represent a novel therapeutic concept to ameliorate disease state in PH.
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effects of riociguat in severe Experimental Pulmonary Hypertension
European Respiratory Journal, 2011Co-Authors: Baktybek Kojonazarov, Norbert Weissmann, Johannespeter Stasch, Ralph T. Schermuly, Hossein Ardeschir Ghofrani, Friedrich Grimminger, Werner Seeger, Michaela LangAbstract:Introduction: The NO-sGC-cGMP signaling pathway is impaired in different cardiovascular diseases, including Pulmonary Hypertension (PH). Riociguat is the first of a new class of drugs, the sGC stimulators. Riociguat has a dual mode of action: it sensitizes sGC to the body's own NO and can also increase sGC activity in the absence of NO, causing vasorelaxation, anti-proliferation and anti-fibrotic effects. Aim: The aim of the study was to investigate the effects of riociguat as compared to the PDE5 inhibitor sildenafil on Pulmonary vascular remodeling in severe Experimental PH. Methods: Angioproliferative PH was induced in rats by combined exposure to the VEGFr antagonist SU5416 and hypoxia. 21 days thereafter, rats were randomized for treatment with riociguat (10 mg/kg), sildenafil (50 mg/kg) or vehicle for the next 14 days. Echocardiography and invasive hemodynamic measurements were performed. Pulmonary vascular remodeling was assessed by histomorphomety. Results: In rats with established PH, RVSP was significantly decreased by treatment with riociguat to 73±4 mmHg (p<0.01) and sildenafil to 80±3 mmHg (p<0.05) as compared to placebo (89±3 mmHg). No significant difference in systemic arterial pressure was detected between placebo and treated animals. Both compounds significantly decreased RV hypertrophy and improved RV function by normalization of TAPSE and Tei index, but effects of riociguat were more pronounced. Riociguat significantly reduced the proportion of occluded arteries, increased proportion of opened arteries and decreased neointima/media ratio. Conclusion: We demonstrated that riociguat effectively suppresses Pulmonary vascular remodeling and significantly improves RV function in an Experimental model of PH.
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effects of riociguat in severe Experimental Pulmonary Hypertension
BMC Pharmacology, 2011Co-Authors: Baktybek Kojonazarov, Norbert Weissmann, Johannespeter Stasch, Ralph T. Schermuly, Hossein Ardeschir Ghofrani, Friedrich Grimminger, Werner Seeger, Michaela LangAbstract:The NO-sGC-cGMP signaling pathway is impaired in different cardiovascular diseases, including Pulmonary Hypertension (PH). Riociguat is the first of a new class of drugs, the soluble guanylate cyclase stimulators. Riociguat has a dual mode of action: it sensitizes sGC to the body’s own NO and can also increase sGC activity in the absence of NO, causing vasorelaxation, anti-proliferation and anti-fibrotic effects. The aim of the study was to investigate the effects of riociguat as compared to the PDE5 inhibitor sildenafil on Pulmonary vascular remodeling in severe Experimental PH.
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activation of soluble guanylate cyclase reverses Experimental Pulmonary Hypertension and vascular remodeling
Circulation, 2006Co-Authors: Rio Dumitrascu, Norbert Weissmann, Johannespeter Stasch, Hossein Ardeschir Ghofrani, Eva Dony, Knut Beuerlein, Harald H H W Schmidt, Mark Jean Gnoth, Friedrich GrimmingerAbstract:Background— Severe Pulmonary Hypertension is a disabling disease with high mortality, characterized by Pulmonary vascular remodeling and right heart hypertrophy. Using wild-type and homozygous endothelial nitric oxide synthase (NOS3−/−) knockout mice with Pulmonary Hypertension induced by chronic hypoxia and rats with monocrotaline-induced Pulmonary Hypertension, we examined whether the soluble guanylate cyclase (sGC) stimulator Bay41-2272 or the sGC activator Bay58-2667 could reverse Pulmonary vascular remodeling. Methods and Results— Both Bay41-2272 and Bay58-2667 dose-dependently inhibited the pressor response of acute hypoxia in the isolated perfused lung system. When wild-type (NOS3+/+) or NOS3−/− mice were housed under 10% oxygen conditions for 21 or 35 days, both strains developed Pulmonary Hypertension, right heart hypertrophy, and Pulmonary vascular remodeling, demonstrated by an increase in fully muscularized peripheral Pulmonary arteries. Treatment of wild-type mice with the activator of sGC, B...
Hossein Ardeschir Ghofrani - One of the best experts on this subject based on the ideXlab platform.
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inhibition of microrna 17 improves lung and heart function in Experimental Pulmonary Hypertension
American Journal of Respiratory and Critical Care Medicine, 2012Co-Authors: Soni Savai Pullamsetti, Norbert Weissmann, Bhola K Dahal, Rajkumar Savai, Hossein Ardeschir Ghofrani, Friedrich Grimminger, Baktybek Kojonazarov, Carmen Doebele, Ariane Fischer, Angelika BonauerAbstract:Rationale: MicroRNAs (miRs) control various cellular processes in tissue homeostasis and disease by regulating gene expression on the posttranscriptional level. Recently, it was demonstrated that the expression of miR-21 and members of the miR-17–92 cluster was significantly altered in Experimental Pulmonary Hypertension (PH).Objectives: To evaluate the therapeutic efficacy and antiremodeling potential of miR inhibitors in the pathogenesis of PH.Methods: We first tested the effects of miR inhibitors (antagomirs), which were specifically designed to block miR-17 (A-17), miR-21 (A-21), and miR-92a (A-92a) in chronic hypoxia-induced PH in mice and A-17 in monocrotaline-induced PH in rats. Moreover, biological function of miR-17 was analyzed in cultured Pulmonary artery smooth muscle cells.Measurements and Main Results: In the PH mouse model, A-17 and A-21 reduced right ventricular systolic pressure, and all antagomirs decreased Pulmonary arterial muscularization. However, only A-17 reduced hypoxia-induced ri...
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role of src tyrosine kinases in Experimental Pulmonary Hypertension
Arteriosclerosis Thrombosis and Vascular Biology, 2012Co-Authors: Soni Savai Pullamsetti, Bhola K Dahal, Rajkumar Savai, E M Berghausen, Swati Dabral, Aleksandra Tretyn, Elsa Butrous, Ghazwan Butrous, Ralf P Brandes, Hossein Ardeschir GhofraniAbstract:Objective—Pulmonary arterial Hypertension is a progressive Pulmonary vascular disorder with high morbidity and mortality. Compelling evidence suggests that receptor tyrosine kinases, such as platelet-derived growth factor (PDGF) are closely involved in the pathogenesis of Pulmonary arterial Hypertension. We investigated the effects of 2 novel PDGF inhibitors, nilotinib/AMN107 (Abl kinases/PDGF receptor inhibitor) and dasatinib/BMS-354825 (Abl kinases/PDGF receptor/Src inhibitor), on the proliferation and migration of Pulmonary arterial smooth muscle cells (PASMCs) and on the hemodynamics and Pulmonary vascular remodeling in Experimental Pulmonary Hypertension, and determined the expression and regulation of Src family kinases. Methods and Results—Human PASMCs were stimulated by PDGF alone or multiple growth factors to induce proliferation and migration in vitro. Dasatinib (0.03 μmol/L), nilotinib (0.3 μmol/L), and imatinib (1 μmol/L) potently inhibited PDGF-induced signal transducer and activator of trans...
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inhibition of microrna 17 improves lung and heart function in Experimental Pulmonary Hypertension
American Thoracic Society International Conference, 2012Co-Authors: Soni Savai Pullamsetti, Norbert Weissmann, Bhola K Dahal, Rajkumar Savai, Hossein Ardeschir Ghofrani, Friedrich Grimminger, Baktybek Kojonazarov, Carmen Doebele, Ariane Fischer, Angelika BonauerAbstract:MicroRNAs (miRs) control various cellular processes in tissue homeostasis and disease by regulating gene expression on the posttranscriptional level. Recently, it was demonstrated that the expression of miR-21 and members of the miR-17-92 cluster was significantly altered in Experimental Hypertension (PH). We evaluated whether inhibition of these miRs may provide a novel therapeutic option. We first tested the effects of miR inhibitors (antagomirs), which were specifically designed to block miR-17 (A-17), -21 (A-21) and -92a (A-92a) in chronic hypoxia-induced PH in mice. A-17 and A-21 reduced right ventricular systolic pressure (RVSP) and all antagomirs decreased Pulmonary arterial muscularization. However, only A-17 reduced hypoxia-induced right ventricular hypertrophy and improved Pulmonary artery acceleration time (PAAT). Therefore, we additionally tested the effects of A-17 in monocrotaline-induced PH in rats. A-17 treatment significantly decreased RVSP and total Pulmonary vascular resistance index, increased PAAT, normalized cardiac output and decreased Pulmonary vascular remodelling. Among the tested miR-17 targets, the cyclin-dependent kinase inhibitor 1A (p21) was upregulated in lungs undergoing A-17 treatment. Likewise, in human Pulmonary artery smooth muscle cells, A-17 increased p21. Overexpression of miR-17 significantly reduced p21 expression and increased proliferation of smooth muscle cells. Our data demonstrate that A-17 improves heart and lung function in Experimental PH by interfering with lung vascular and right ventricular remodeling. Thus, inhibition of miR-17 may represent a novel therapeutic concept to ameliorate disease state in PH.
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par 2 inhibition reverses Experimental Pulmonary Hypertension
Circulation Research, 2012Co-Authors: Grazyna Kwapiszewska, Bhola K Dahal, Ralph T. Schermuly, Hossein Ardeschir Ghofrani, Baktybek Kojonazarov, Philipp Markart, Leigh M Marsh, Christian Taube, Andreas Meinhardt, Martin SteinhoffAbstract:Rationale: A hallmark of the vascular remodeling process underlying Pulmonary Hypertension (PH) is the aberrant proliferation and migration of Pulmonary arterial smooth muscle cells (PASMC). Accumulating evidence suggests that mast cell mediators play a role in the pathogenesis of PH. Objective: In the present study we investigated the importance of protease-activated receptor (PAR)–2 and its ligand mast cell tryptase in the development of PH. Methods and Results: Our results revealed strong increase in PAR-2 and tryptase expression in the lungs of idiopathic Pulmonary arterial Hypertension (IPAH) patients, hypoxia-exposed mice, and monocrotaline (MCT)–treated rats. Elevated tryptase levels were also detected in plasma samples from IPAH patients. Hypoxia and platelet-derived growth factor (PDGF)–BB upregulated PAR-2 expression in PASMC. This effect was reversed by HIF (hypoxia inducible factor)–1α depletion, PDGF-BB neutralizing antibody, or the PDGF-BB receptor antagonist Imatinib. Attenuation of PAR-2 expression was also observed in smooth muscle cells of Pulmonary vessels of mice exposed to hypoxia and rats challenged with MCT in response to Imatinib treatment. Tryptase induced PASMC proliferation and migration as well as enhanced synthesis of fibronectin and matrix metalloproteinase-2 in a PAR-2- and ERK1/2-dependent manner, suggesting that PAR-2-dependent signaling contributes to vascular remodeling by various mechanisms. Furthermore, PAR-2 −/− mice were protected against hypoxia-induced PH, and PAR-2 antagonist application reversed established PH in the hypoxia mouse model. Conclusions: Our study identified a novel role of PAR-2 in vascular remodeling in the lung. Interference with this pathway may offer novel therapeutic options for the treatment of PH.
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effects of riociguat in severe Experimental Pulmonary Hypertension
European Respiratory Journal, 2011Co-Authors: Baktybek Kojonazarov, Norbert Weissmann, Johannespeter Stasch, Ralph T. Schermuly, Hossein Ardeschir Ghofrani, Friedrich Grimminger, Werner Seeger, Michaela LangAbstract:Introduction: The NO-sGC-cGMP signaling pathway is impaired in different cardiovascular diseases, including Pulmonary Hypertension (PH). Riociguat is the first of a new class of drugs, the sGC stimulators. Riociguat has a dual mode of action: it sensitizes sGC to the body's own NO and can also increase sGC activity in the absence of NO, causing vasorelaxation, anti-proliferation and anti-fibrotic effects. Aim: The aim of the study was to investigate the effects of riociguat as compared to the PDE5 inhibitor sildenafil on Pulmonary vascular remodeling in severe Experimental PH. Methods: Angioproliferative PH was induced in rats by combined exposure to the VEGFr antagonist SU5416 and hypoxia. 21 days thereafter, rats were randomized for treatment with riociguat (10 mg/kg), sildenafil (50 mg/kg) or vehicle for the next 14 days. Echocardiography and invasive hemodynamic measurements were performed. Pulmonary vascular remodeling was assessed by histomorphomety. Results: In rats with established PH, RVSP was significantly decreased by treatment with riociguat to 73±4 mmHg (p<0.01) and sildenafil to 80±3 mmHg (p<0.05) as compared to placebo (89±3 mmHg). No significant difference in systemic arterial pressure was detected between placebo and treated animals. Both compounds significantly decreased RV hypertrophy and improved RV function by normalization of TAPSE and Tei index, but effects of riociguat were more pronounced. Riociguat significantly reduced the proportion of occluded arteries, increased proportion of opened arteries and decreased neointima/media ratio. Conclusion: We demonstrated that riociguat effectively suppresses Pulmonary vascular remodeling and significantly improves RV function in an Experimental model of PH.
Nicholas W Morrell - One of the best experts on this subject based on the ideXlab platform.
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role of the aryl hydrocarbon receptor in sugen 5416 induced Experimental Pulmonary Hypertension
American Journal of Respiratory Cell and Molecular Biology, 2017Co-Authors: Afshan Dean, Nicholas W Morrell, Teja Gregorc, Craig K Docherty, Katie Y Harvey, Margaret Nilsen, Margaret R MacleanAbstract:Rats dosed with the vascular endothelial growth factor inhibitor Sugen 5416 (Su), subjected to hypoxia, and then restored to normoxia have become a widely used model of Pulmonary arterial Hypertension (PAH). However, the mechanism by which Su exacerbates Pulmonary Hypertension is unclear. We investigated Su activation of the aryl hydrocarbon receptor (AhR) in human Pulmonary artery smooth muscle cells (hPASMCs) and blood outgrowth endothelial cells (BOECs) from female patients with PAH. We also examined the effect of AhR on aromatase and estrogen levels in the lung. Protein and mRNA analyses demonstrated that CYP1A1 was very highly induced in the lungs of Su/hypoxic (Su/Hx) rats. The AhR antagonist CH223191 (8 mg/kg/day) reversed the development of PAH in this model in vivo and normalized lung CYP1A1 expression. Increased lung aromatase and estrogen levels in Su/Hx rats were also normalized by CH223191, as was AhR nuclear translocator (ARNT [HIF-1β]), which is shared by HIF-1α and AhR. Su reduced HIF-1α expression in hPASMCs. Su induced proliferation in BOECs and increased apoptosis in human Pulmonary microvascular ECs and also induced translocation of AhR to the nucleus in hPASMCs. Under normoxic conditions, hPASMCs did not proliferate to Su. However, when grown in hypoxia (1%), Su induced hPASMC proliferation. In combination with hypoxia, Su is proliferative in hPASMCs and BOECs from patients with PAH, and Su/Hx-induced PAH in rats may be facilitated by AhR-induced CYP1A1, ARNT, and aromatase. Inhibition of AhR may be a novel approach to the treatment of Pulmonary Hypertension.
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chloroquine prevents progression of Experimental Pulmonary Hypertension via inhibition of autophagy and lysosomal bone morphogenetic protein type ii receptor degradation
Circulation Research, 2013Co-Authors: Lu Long, Xudong Yang, Mark Southwood, Stefan J Marciniak, Benjamin J Dunmore, Nicholas W MorrellAbstract:Rationale: Pulmonary arterial Hypertension (PAH) is characterized by excessive proliferation and apoptosis resistance in Pulmonary artery smooth muscle cells (PASMCs). Objective: We reasoned that chloroquine, based on its ability to inhibit autophagy and block lysosomal degradation of the bone morphogenetic protein type II receptor (BMPR-II), might exert beneficial effects in this disease. Methods and Results: PAH was induced in male Sprague–Dawley rats by administering monocrotaline. The induction of PAH was associated with changes in lung expression of LC3B-II, ATG5, and p62, consistent with increased autophagy, and decreased BMPR-II protein expression. Administration of chloroquine prevented the development of PAH, right ventricular hypertrophy, and vascular remodelling after monocrotaline, and prevented progression of established PAH in this model. Similar results were obtained with hydroxychloroquine. Chloroquine treatment increased whole lung and PASMC p62 protein levels consistent with inhibition of autophagy, and increased levels of BMPR-II protein. Chloroquine inhibited proliferation and increased apoptosis of PASMCs in vivo. In cultured rat PASMCs we confirmed that chloroquine both inhibited autophagy pathways and increased expression of BMPR-II protein via lysosomal inhibition. Consistent with the in vivo findings, chloroquine inhibited the proliferation and stimulated apoptosis of rat PASMCs in vitro, with no effect on endothelial cell proliferation or survival. Moreover, direct inhibition of autophagy pathways by ATG5 small interfering RNA knockdown inhibited proliferation of rat PASMCs. Conclusions: Chloroquine and hydroxychloroquine exert beneficial effects in Experimental PAH. The mechanism of action includes inhibition of autophagy pathways and inhibition of lysosomal degradation of BMPR-II. # Novelty and Significance {#article-title-45}
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chloroquine prevents progression of Experimental Pulmonary Hypertension via inhibition of autophagy and lysosomal bmpr ii degradation
Circulation Research, 2013Co-Authors: Lu Long, Xudong Yang, Mark Southwood, Junyu Lu, Stefan J Marciniak, Benjamin J Dunmore, Nicholas W MorrellAbstract:Rationale: Pulmonary arterial Hypertension (PAH) is characterised by excessive proliferation and apoptosis resistance in Pulmonary artery smooth muscle cells (PASMCs). Objective: We reasoned that chloroquine, based on its ability to inhibit autophagy and block lysosomal degradation of the bone morphogenetic protein type II receptor (BMPR-II), might exert beneficial effects in this disease. Methods and Results: PAH was induced in male Sprague-Dawley rats by administration of monocrotaline (MCT). The induction of PAH was associated with changes in lung expression of LC3B-II, ATG5 and p62, consistent with increased autophagy, and decreased BMPR-II protein expression. Administration of chloroquine prevented the development of PAH, right ventricular hypertrophy and vascular remodelling following MCT, and prevented progression of established PAH in this model. Similar results were obtained with hydroxychloroquine. Chloroquine treatment increased whole lung and PASMC p62 protein levels consistent with inhibition of autophagy, and increased levels of BMPR-II protein. Chloroquine inhibited proliferation and increased apoptosis of PASMCs in vivo. In cultured rat PASMCs we confirmed that chloroquine both inhibited autophagy pathways and increased expression of BMPR-II protein via lysosomal inhibition. Consistent with the in vivo findings, chloroquine inhibited the proliferation and stimulated apoptosis of rat PASMCs in vitro, with no effect on endothelial cell proliferation or survival. Moreover, direct inhibition of autophagy pathways by ATG5 siRNA knockdown inhibited proliferation of rat PASMCs. Conclusions: Chloroquine and hydroxychloroquine exert beneficial effects in Experimental PAH. The mechanism of action includes inhibition of autophagy pathways and inhibition of lysosomal degradation of BMPR-II.
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sildenafil potentiates bone morphogenetic protein signaling in Pulmonary arterial smooth muscle cells and in Experimental Pulmonary Hypertension
Arteriosclerosis Thrombosis and Vascular Biology, 2013Co-Authors: Jun Yang, Ralph T. Schermuly, Rafia S Allamki, Astrid Weiss, Joachim Berk, Nicholas W MorrellAbstract:Objective— Mutations in the bone morphogenetic protein type II receptor (BMPR-II) are responsible for the majority of cases of heritable Pulmonary arterial Hypertension (PAH), and BMPR-II deficiency contributes to idiopathic and Experimental forms of PAH. Sildenafil, a potent type-5 nucleotide-dependent phosphodiesterase inhibitor, is an established treatment for PAH, but whether sildenafil affects bone morphogenetic protein (BMP) signaling in the Pulmonary circulation remains unknown. Methods and Results— Studies were undertaken in human Pulmonary arterial smooth muscle cells (PASMCs) and in vivo in the monocrotaline rat model of PAH. In PASMCs, sildenafil enhanced BMP4-induced phosphorylation of Smad1/5, Smad nuclear localization, and Inhibitor of DNA binding protein 1 gene and protein expression. This effect was mimicked by 8-bromo-cyclic GMP. Pharmacological inhibition or small interfering RNA knockdown of cyclic GMP-dependent protein kinase I inhibited the effect of sildenafil on BMP signaling. In functional studies, we observed that sildenafil potentiated the antiproliferative effects of BMP4 on PASMC proliferation. Furthermore, sildenafil restored the antiproliferative response to BMP4 in PASMCs harboring mutations in BMPR-II. In the monocrotaline rat model of PAH, which is characterized by BMPR-II deficiency, sildenafil prevented the development of Pulmonary Hypertension and vascular remodeling, and partly restored Smad1/5 phosphorylation and Inhibitor of DNA binding protein 1 gene expression in vivo in monocrotaline exposed rat lungs. Conclusion— Sildenafil enhances canonical BMP signaling via cyclic GMP and cyclic GMP-dependent protein kinase I in vitro and in vivo, and partly restores deficient BMP signaling in BMPR-II mutant PASMCs. Our findings demonstrate a novel mechanism of action of sildenafil in the treatment of PAH and suggest that targeting BMP signaling may be beneficial in this disease.
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inflammation growth factors and Pulmonary vascular remodeling
Journal of the American College of Cardiology, 2009Co-Authors: Paul M Hassoun, Peter Lloyd Jones, Luc Mouthon, Joan Albert Barbera, Saadia Eddahibi, Sonia C Flores, Michael L Maitland, Evangelos D Michelakis, Nicholas W MorrellAbstract:Inflammatory processes are prominent in various types of human and Experimental Pulmonary Hypertension (PH) and are increasingly recognized as major pathogenic components of Pulmonary vascular remodeling. Macrophages, T and B lymphocytes, and dendritic cells are present in the vascular lesions of PH, whether in idiopathic Pulmonary arterial Hypertension (PAH) or PAH related to more classical forms of inflammatory syndromes such as connective tissue diseases, human immunodeficiency virus (HIV), or other viral etiologies. Similarly, the presence of circulating chemokines and cytokines, viral protein components (e.g., HIV-1 Nef), and increased expression of growth (such as vascular endothelial growth factor and platelet-derived growth factor) and transcriptional (e.g., nuclear factor of activated T cells or NFAT) factors in these patients are thought to contribute directly to further recruitment of inflammatory cells and proliferation of smooth muscle and endothelial cells. Other processes, such as mitochondrial and ion channel dysregulation, seem to convey a state of cellular resistance to apoptosis; this has recently emerged as a necessary event in the pathogenesis of Pulmonary vascular remodeling. Thus, the recognition of complex inflammatory disturbances in the vascular remodeling process offers potential specific targets for therapy and has recently led to clinical trials investigating, for example, the use of tyrosine kinase inhibitors. This paper provides an overview of specific inflammatory pathways involving cells, chemokines and cytokines, cellular dysfunctions, growth factors, and viral proteins, highlighting their potential role in Pulmonary vascular remodeling and the possibility of future targeted therapy.
