11 results on '"Dietz CT"'
Search Results
2. Expression of the CTLA-4 ligand CD86 on plasmacytoid dendritic cells (pDC) predicts risk of disease recurrence after treatment discontinuation in CML.
- Author
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Schütz C, Inselmann S, Saussele S, Dietz CT, Mu Ller MC, Eigendorff E, Brendel CA, Metzelder SK, Bru Mmendorf TH, Waller C, Dengler J, Goebeler ME, Herbst R, Freunek G, Hanzel S, Illmer T, Wang Y, Lange T, Finkernagel F, Hehlmann R, Huber M, Neubauer A, Hochhaus A, Guilhot J, Xavier Mahon F, Pfirrmann M, and Burchert A
- Subjects
- Adult, Aged, B7-2 Antigen genetics, Biomarkers, Cell Count, Dendritic Cells immunology, Female, Gene Expression, Humans, Immunophenotyping, Kaplan-Meier Estimate, Leukemia, Myelogenous, Chronic, BCR-ABL Positive diagnosis, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive mortality, Male, Middle Aged, Prognosis, Protein Kinase Inhibitors therapeutic use, Recurrence, Remission Induction, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism, Treatment Outcome, Young Adult, B7-2 Antigen metabolism, CTLA-4 Antigen metabolism, Dendritic Cells metabolism, Leukemia, Myelogenous, Chronic, BCR-ABL Positive metabolism
- Abstract
It is unknown, why only a minority of chronic myeloid leukemia (CML) patients sustains treatment free remission (TFR) after discontinuation of tyrosine kinase inhibitor (TKI) therapy in deep molecular remission (MR). Here we studied, whether expression of the T-cell inhibitory receptor (CTLA-4)-ligand CD86 (B7.2) on plasmacytoid dendritic cells (pDC) affects relapse risk after TKI cessation. CML patients in MR displayed significantly higher CD86
+ pDC frequencies than normal donors (P<0.0024), whereas TFR patients had consistently low CD86+ pDC (n=12). This suggested that low CD86+ pDC might be predictive of TFR. Indeed, in a prospective analysis of 122 patients discontinuing their TKI within the EURO-SKI trial, the one-year relapse-free survival (RFS) was 30.1% (95% CI 15.6-47.9) for patients with >95 CD86+ pDC per 105 lymphocytes, but 70.0% (95% CI 59.3-78.3) for patients with <95 CD86+ pDC (hazard ratio (HR) 3.4, 95%- CI: 1.9-6.0; P<0.0001). Moreover, only patients with <95 CD86+ pDC derived a significant benefit from longer (>8 years) TKI exposure before discontinuation (HR 0.3, 95% CI 0.1-0.8; P=0.0263). High CD86+ pDC counts significantly correlated with leukemia-specific CD8+ T- cell exhaustion (Spearman correlation: 0.74, 95%-CI: 0.21-0.92; P=0.0098). Our data demonstrate that CML patients with high CD86+ pDC counts have a higher risk of relapse after TKI discontinuation.- Published
- 2017
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3. Fusion of PDGFRB to MPRIP, CPSF6, and GOLGB1 in three patients with eosinophilia-associated myeloproliferative neoplasms.
- Author
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Naumann N, Schwaab J, Metzgeroth G, Jawhar M, Haferlach C, Göhring G, Schlegelberger B, Dietz CT, Schnittger S, Lotfi S, Gärtner M, Dang TA, Hofmann WK, Cross NC, Reiter A, and Fabarius A
- Subjects
- Aged, Aged, 80 and over, Antineoplastic Agents therapeutic use, Chromosomes, Human, Pair 12 genetics, Chromosomes, Human, Pair 17 genetics, Chromosomes, Human, Pair 3 genetics, Chromosomes, Human, Pair 5 genetics, Cytogenetic Analysis, Eosinophilia drug therapy, Eosinophilia pathology, Golgi Matrix Proteins, Humans, Imatinib Mesylate therapeutic use, In Situ Hybridization, Fluorescence, Male, Middle Aged, Myeloproliferative Disorders drug therapy, Myeloproliferative Disorders pathology, Polymerase Chain Reaction, Remission Induction, Adaptor Proteins, Signal Transducing genetics, Eosinophilia genetics, Gene Fusion, Membrane Proteins genetics, Myeloproliferative Disorders genetics, Receptor, Platelet-Derived Growth Factor beta genetics, Translocation, Genetic, mRNA Cleavage and Polyadenylation Factors genetics
- Abstract
In eosinophilia-associated myeloproliferative neoplasms (MPN-eo), constitutive activation of protein tyrosine kinases (TK) as consequence of translocations, inversions, or insertions and creation of TK fusion genes is recurrently observed. The most commonly involved TK and their potential TK inhibitors include PDGFRA at 4q12 or PDGFRB at 5q33 (imatinib), FGFR1 at 8p11 (ponatinib), and JAK2 at 9p24 (ruxolitinib). We here report the identification of three new PDGFRB fusion genes in three male MPN-eo patients: MPRIP-PDGFRB in a case with t(5;17)(q33;p11), CPSF6-PDGFRB in a case with t(5;12)(q33;q15), and GOLGB1-PDGFRB in a case with t(3;5)(q13;q33). The fusion proteins identified by 5'-rapid amplification of cDNA ends polymerase chain reaction (PCR) or DNA-based long distance inverse PCR are predicted to contain the TK domain of PDGFRB. The partner genes contain domains like coiled-coil structures, which are likely to cause dimerization and activation of the TK. In all patients, imatinib induced rapid and durable complete remissions., (© 2015 Wiley Periodicals, Inc.)
- Published
- 2015
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4. Impact of unbalanced minor route versus major route karyotypes at diagnosis on prognosis of CML.
- Author
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Fabarius A, Kalmanti L, Dietz CT, Lauseker M, Rinaldetti S, Haferlach C, Göhring G, Schlegelberger B, Jotterand M, Hanfstein B, Seifarth W, Hänel M, Köhne CH, Lindemann HW, Berdel WE, Staib P, Müller MC, Proetel U, Balleisen L, Goebeler ME, Dengler J, Falge C, Kanz L, Burchert A, Kneba M, Stegelmann F, Pfreundschuh M, Waller CF, Spiekermann K, Brümmendorf TH, Edinger M, Hofmann WK, Pfirrmann M, Hasford J, Krause S, Hochhaus A, Saußele S, and Hehlmann R
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Disease-Free Survival, Female, Humans, Karyotyping, Male, Middle Aged, Survival Rate, Abnormal Karyotype, Leukemia, Myelogenous, Chronic, BCR-ABL Positive diagnosis, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive mortality, Philadelphia Chromosome
- Abstract
Major route additional cytogenetic aberrations (ACA) at diagnosis of chronic myeloid leukaemia (CML) indicate an increased risk of progression and shorter survival. Since major route ACA are almost always unbalanced, it is unclear whether other unbalanced ACA at diagnosis also confer an unfavourable prognosis. On the basis of 1348 Philadelphia chromosome-positive chronic phase patients of the randomized CML study IV, we examined the impact of unbalanced minor route ACA at diagnosis versus major route ACA on prognosis. At diagnosis, 1175 patients (87.2 %) had a translocation t(9;22)(q34;q11) and 74 (5.5 %) a variant translocation t(v;22) only, while a loss of the Y chromosome (-Y) was present in addition in 44 (3.3 %), balanced or unbalanced minor route ACA each in 17 (1.3 %) and major route ACA in 21 (1.6 %) cases. Patients with unbalanced minor route ACA had no significantly different cumulative incidences of complete cytogenetic remission or major molecular remission and no significantly different progression-free survival (PFS) or overall survival (OS) than patients with t(9;22), t(v;22), -Y and balanced minor route karyotypes. In contrast, patients with major route ACA had a shorter OS and PFS than all other groups (all pairwise comparisons to each of the other groups: p ≤ 0.015). Five-year survival probabilities were for t(9;22) 91.4 % (95 % CI 89.5-93.1), t(v; 22) 87 % (77.2-94.3), -Y 89.0 % (76.7-97.0), balanced 100 %, unbalanced minor route 92.3 % (72.4-100) and major route 52.2 % (28.2-75.5). We conclude that only major route, but not balanced or unbalanced minor route ACA at diagnosis, has a negative impact on prognosis of CML.
- Published
- 2015
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5. Safety and efficacy of imatinib in CML over a period of 10 years: data from the randomized CML-study IV.
- Author
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Kalmanti L, Saussele S, Lauseker M, Müller MC, Dietz CT, Heinrich L, Hanfstein B, Proetel U, Fabarius A, Krause SW, Rinaldetti S, Dengler J, Falge C, Oppliger-Leibundgut E, Burchert A, Neubauer A, Kanz L, Stegelmann F, Pfreundschuh M, Spiekermann K, Scheid C, Pfirrmann M, Hochhaus A, Hasford J, and Hehlmann R
- Subjects
- Aged, Antineoplastic Agents adverse effects, Benzamides adverse effects, Disease Progression, Disease-Free Survival, Female, Follow-Up Studies, Fusion Proteins, bcr-abl genetics, Fusion Proteins, bcr-abl metabolism, Humans, Imatinib Mesylate, Interferon-alpha therapeutic use, Male, Middle Aged, Pilot Projects, Piperazines adverse effects, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors adverse effects, Pyrimidines adverse effects, Remission Induction, Treatment Outcome, Antineoplastic Agents administration & dosage, Benzamides administration & dosage, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Piperazines administration & dosage, Pyrimidines administration & dosage
- Abstract
Tyrosine kinase inhibitors (TKI) have changed the natural course of chronic myeloid leukemia (CML). With the advent of second-generation TKI safety and efficacy issues have gained interest. The randomized CML - Study IV was used for a long-term evaluation of imatinib (IM). 1503 patients have received IM, 1379 IM monotherapy. After a median observation of 7.1 years, 965 patients (64%) still received IM. At 10 years, progression-free survival was 82%, overall survival 84%, 59% achieved MR(5), 72% MR(4.5), 81% MR(4), 89% major molecular remission and 92% MR(2) (molecular equivalent to complete cytogenetic remission). All response levels were reached faster with IM800 mg except MR(5). Eight-year probabilities of adverse drug reactions (ADR) were 76%, of grades 3-4 22%, of non-hematologic 73%, and of hematologic 28%. More ADR were observed with IM800 mg and IM400 mg plus interferon α (IFN). Most patients had their first ADR early with decreasing frequency later on. No new late toxicity was observed. ADR to IM are frequent, but mostly mild and manageable, also with IM 800 mg and IM 400 mg+IFN. The deep molecular response rates indicate that most patients are candidates for IM discontinuation. After 10 years, IM continues to be an excellent initial choice for most patients with CML.
- Published
- 2015
- Full Text
- View/download PDF
6. Equivalence of BCR-ABL transcript levels with complete cytogenetic remission in patients with chronic myeloid leukemia in chronic phase.
- Author
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Lauseker M, Hanfstein B, Haferlach C, Schnittger S, Pfirrmann M, Fabarius A, Schlegelberger B, Saußele S, Dietz CT, Erben P, Hehlmann R, Hasford J, Hochhaus A, and Müller MC
- Subjects
- Biomarkers, Tumor genetics, Fusion Proteins, bcr-abl genetics, Gene Expression, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Leukemia, Myelogenous, Chronic, BCR-ABL Positive therapy, Molecular Diagnostic Techniques, RNA, Messenger genetics, Remission Induction, Biomarkers, Tumor blood, Fusion Proteins, bcr-abl blood, Leukemia, Myelogenous, Chronic, BCR-ABL Positive blood, RNA, Messenger blood
- Abstract
Purpose: Chronic myeloid leukemia (CML) patients are monitored by both cytogenetic and molecular assessments, although present guidelines appear to switch from cytogenetic to molecular criteria. Due to the increasing use of molecular measurements, it was the aim of this work to identify a BCR-ABL level according to the international scale (BCR-ABL(IS)) as an equivalent substitute for complete cytogenetic remission (CCyR)., Methods: In total, 1,329 paired data from 557 patients of the German CML-Study IV were evaluated. The data set was divided into a learning set and a validation set. The best cutoff was determined applying a minimal p value approach to the Fisher test., Results: In the learning set, we found BCR-ABL(IS) values between 0.2 and 1.1 % were well suited for predicting a CCyR. In the validation set, the cutoff level of 1 % led to a mean concordance rate of 90.1 %., Conclusions: Our results suggest that there is no one-to-one cutoff for BCR-ABL(IS) representing CCyR, but we advise to use the 1 % BCR-ABL(IS) in order to avoid misclassification of CCyR patients.
- Published
- 2014
- Full Text
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7. Kelch-like ECT2-interacting protein KLEIP regulates late-stage pulmonary maturation via Hif-2α in mice.
- Author
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Woik N, Dietz CT, Schäker K, and Kroll J
- Subjects
- Animals, Glucocorticoids therapeutic use, Lung Diseases drug therapy, Mice, Microfilament Proteins genetics, Respiratory Insufficiency, Survival Rate, Basic Helix-Loop-Helix Transcription Factors physiology, Lung growth & development, Microfilament Proteins physiology
- Abstract
Respiratory distress syndrome (RDS) caused by preterm delivery is a major clinical problem with limited mechanistic insight. Late-stage embryonic lung development is driven by hypoxia and the hypoxia-inducible transcription factors Hif-1α and Hif-2α, which act as important regulators for lung development. Expression of the BTB-and kelch-domain-containing (BTB-kelch) protein KLEIP (Kelch-like ECT2-interacting protein; also named Klhl20) is controlled by two hypoxia response elements, and KLEIP regulates stabilization and transcriptional activation of Hif-2α. Based on the available data, we hypothesized an essential role for KLEIP in murine lung development and function. Therefore, we have performed a functional, histological, mechanistic and interventional study in embryonic and neonatal KLEIP(-/-) mice. Here, we show that about half of the KLEIP(-/-) neonates die due to respiratory failure that is caused by insufficient aeration, reduced septal thinning, reduced glycogenolysis, type II pneumocyte immaturity and reduced surfactant production. Expression analyses in embryonic day (E) 18.5 lungs identified KLEIP in lung capillaries, and showed strongly reduced mRNA and protein levels for Hif-2α and VEGF; such reduced levels are associated with embryonic endothelial cell apoptosis and lung bleedings. Betamethasone injection in pregnant females prevented respiratory failure in KLEIP(-/-) neonates, normalized lung maturation, vascularization, aeration and function, and increased neonatal Hif-2α expression. Thus, the experimental study shows that respiratory failure in KLEIP(-/-) neonates is determined by insufficient angiocrine Hif-2α-VEGF signaling and that betamethasone activates this newly identified signaling cascade in late-stage embryonic lung development., (© 2014. Published by The Company of Biologists Ltd.)
- Published
- 2014
- Full Text
- View/download PDF
8. Expression of transketolase-like gene 1 (TKTL1) depends on disease phase in patients with chronic myeloid leukaemia (CML).
- Author
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Philipp M, Schwaab J, Dietz CT, Hanfstein B, Kalmanti L, Munjal U, Mossner M, Nowak D, Seifarth W, Hofmann WK, Hochhaus A, Müller MC, and Erben P
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Antineoplastic Agents therapeutic use, Benzamides therapeutic use, Down-Regulation, Female, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Leukemic, Humans, Imatinib Mesylate, Male, Middle Aged, Piperazines therapeutic use, Predictive Value of Tests, Protein Kinase Inhibitors therapeutic use, Pyrimidines therapeutic use, Real-Time Polymerase Chain Reaction, Transketolase genetics, Granulocytes enzymology, Leukemia, Myelogenous, Chronic, BCR-ABL Positive enzymology, Transketolase metabolism
- Abstract
Purpose: Overexpression of transketolase-like gene 1 (TKTL1) on RNA and protein level has been linked to tumour progression, metastasis and unfavourable patient outcome in many solid tumours. Chronic myeloid leukaemia (CML) cells show metabolic characteristics resembling deviations observed in TKTL1 overexpressing solid tumour cells. We therefore sought to evaluate TKTL1 gene expression in different phases of CML., Methods: A total of 120 peripheral blood samples from 69 patients in various phases of CML and 21 healthy individuals were investigated. TKTL1 expression levels were determined by real-time quantitative polymerase chain reaction using LightCycler technology and normalised against beta-glucuronidase expression., Results: A significantly lower TKTL1 expression was found in chronic phase (CP) CML patients compared to healthy controls. Lowest expression levels were observed in patients during blast crisis (BC). Baseline TKTL1 expression in CP patients did not have value in prognostication of subsequent favourable or dismal outcome. Further, more mature granulocytes showed significantly higher TKTL1 expression compared to immature CD34+ and CD34-/CD33+ cells both in healthy controls and in CML patients., Conclusion: TKTL1 expression levels appear to decline in the course of CML with lowest levels during BC. A potential reason is a shift of TKTL1-high-expressing mature granulocytes towards TKTL1-low-expressing immature cells and blasts.
- Published
- 2014
- Full Text
- View/download PDF
9. KLEIP deficiency in mice causes progressive corneal neovascular dystrophy.
- Author
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Hahn N, Dietz CT, Kühl S, Vossmerbaeumer U, and Kroll J
- Subjects
- Adaptor Proteins, Signal Transducing, Animals, Carrier Proteins biosynthesis, Cornea pathology, Corneal Neovascularization metabolism, Corneal Neovascularization pathology, Corneal Opacity etiology, Corneal Opacity genetics, Disease Models, Animal, Disease Progression, Genotype, Mice, Mice, Inbred C57BL, Mice, Transgenic, Real-Time Polymerase Chain Reaction, Carrier Proteins genetics, Cornea metabolism, Corneal Neovascularization complications, Corneal Opacity pathology, Gene Expression Regulation, RNA, Messenger genetics
- Abstract
Purpose: The BTB-kelch protein KLEIP/KLHL20 is an actin binding protein that regulates cell-cell contact formation and cell migration. The aim of our study was to characterize KLEIP's function in ocular health and disease in mice., Methods: KLEIP(-/-) mice were generated, and corneas were examined histologically and stained for keratin-1, loricrin, keratin-12, keratin-14, CD31, LYVE-1, F4/80, E-cadherin, and Ki67. Corneal abrasions were performed after eyelid opening., Results: Corneas of KLEIP(+/+) and KLEIP(-/-) mice were indistinguishable at birth. After eyelid opening corneal epithelial hyperplasia started to manifest in KLEIP(-/-) mice, showing a progressive epithelial metaplasia leading to total corneal opacity. In KLEIP(-/-) mice the initial stratified squamous corneal epithelium was altered to an epidermal histo-architecture showing several superficial keratinized cells, cell infiltrations into the stroma, and several apoptotic cells. Skin markers keratin 1 and loricrin were positive, and surface disease was accompanied by deep stromal vascularization. Expression analysis for E-cadherin in KLEIP(-/-) corneas showed acellular areas in the squamous epithelium, indicating a progressive fragile corneal integrity. Removal of the virgin epithelium accelerated strongly development of the epithelial and stromal alterations, identifying mechanical injuries as the major trigger for corneal dystrophy formation and scarification in KLEIP(-/-) mice., Conclusions: The data identify KLEIP as an important molecule regulating corneal epithelial integrity.
- Published
- 2012
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10. The Rac1 regulator ELMO1 controls vascular morphogenesis in zebrafish.
- Author
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Epting D, Wendik B, Bennewitz K, Dietz CT, Driever W, and Kroll J
- Subjects
- Amino Acid Sequence, Animals, Animals, Genetically Modified, Blood Vessels cytology, Cattle, Cell Line, Endothelial Cells cytology, Endothelial Cells physiology, Humans, Molecular Sequence Data, Phylogeny, Zebrafish, rac GTP-Binding Proteins, Adaptor Proteins, Signal Transducing physiology, Blood Vessels embryology, Zebrafish Proteins physiology, rac1 GTP-Binding Protein physiology
- Abstract
Rationale: Angiogenesis is regulated by the small GTPase Rac1. The ELMO1/DOCK180 complex forms a guanine nucleotide exchange factor for Rac1, regulating its activation during cell migration in different biological systems., Objective: To investigate the function of ELMO1/DOCK180 in vascular development., Methods and Results: In situ hybridization studies for elmo1 identified a vascular and neuronal expression in zebrafish. Morpholino-based expression silencing of elmo1 severely impaired the formation of the vasculature, including intersomitic vessels, the dorsal longitudinal anastomotic vessel, the parachordal vessel, and the development of the thoracic duct in tg(fli1:EGFP) embryos. Mechanistically, we identified Netrin-1 and its receptor Unc5B as upstream activators of the ELMO1/DOCK180 complex, regulating its functional interaction and leading to Rac1 activation in endothelial cells and vessel formation in zebrafish., Conclusions: Our data have identified a novel signaling cascade regulating vasculature formation in zebrafish.
- Published
- 2010
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11. Inhibition of Rho-dependent kinases ROCK I/II activates VEGF-driven retinal neovascularization and sprouting angiogenesis.
- Author
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Kroll J, Epting D, Kern K, Dietz CT, Feng Y, Hammes HP, Wieland T, and Augustin HG
- Subjects
- 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine pharmacology, Angiogenesis Inhibitors pharmacology, Animals, Animals, Newborn, Cells, Cultured, Disease Models, Animal, Dose-Response Relationship, Drug, Endothelial Cells drug effects, Endothelial Cells enzymology, Humans, Mice, Mitogen-Activated Protein Kinase 1 metabolism, Mitogen-Activated Protein Kinase 3 metabolism, Oxygen, Phthalazines pharmacology, Pyridines pharmacology, RNA Interference, RNA, Small Interfering metabolism, Receptors, Vascular Endothelial Growth Factor antagonists & inhibitors, Receptors, Vascular Endothelial Growth Factor metabolism, Retinal Neovascularization chemically induced, Retinal Neovascularization enzymology, rho-Associated Kinases genetics, rho-Associated Kinases metabolism, 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine analogs & derivatives, Angiogenesis Inducing Agents pharmacology, Neovascularization, Physiologic drug effects, Protein Kinase Inhibitors pharmacology, Retinal Neovascularization physiopathology, Vascular Endothelial Growth Factor A metabolism, rho-Associated Kinases antagonists & inhibitors
- Abstract
Vascular endothelial growth factor (VEGF) is an endothelial-specific growth factor that activates the small GTPase RhoA. While the role of RhoA for VEGF-driven endothelial migration and angiogenesis has been studied in detail, the function of its target proteins, the Rho-dependent kinases ROCK I and II, are controversially discussed. Using the mouse model of oxygen-induced proliferative retinopathy, ROCK I/II inhibition by H-1152 resulted in increased angiogenesis. This enhanced angiogenesis, however, was completely blocked by the VEGF-receptor antagonist PTK787/ZK222584. Loss-of-function experiments in endothelial cells revealed that inhibition of ROCK I/II using the pharmacological inhibitor H-1152 and ROCK I/II-specific small-interfering RNAs resulted in a rise of VEGF-driven sprouting angiogenesis. These functional data were biochemically substantiated by showing an enhanced VEGF-receptor kinase insert domain receptor phosphorylation and extracellular signal-regulated kinase 1/2 activation after inhibition of ROCK I/II. Thus our data identify that the inhibition of Rho-dependent kinases ROCK I/II activates angiogenesis both, in vitro and in vivo.
- Published
- 2009
- Full Text
- View/download PDF
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