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Activin-like kinase 5 (ALK5) mediates abnormal proliferation of vascular smooth muscle cells from patients with familial pulmonary arterial hypertension and is involved in the progression of experimental pulmonary arterial hypertension induced by monocrotaline Thomas M; Docx C; Holmes AM; Beach S; Duggan N; England K; Leblanc C; Lebret C; Schindler F; Raza F; Walker C; Crosby A; Davies RJ; Morrell NW; Budd DCAm J Pathol 2009[Feb]; 174 (2): 380-9Mutations in the gene for the transforming growth factor (TGF)-beta superfamily receptor, bone morphogenetic protein receptor II, underlie heritable forms of pulmonary arterial hypertension (PAH). Aberrant signaling via TGF-beta receptor I/activin receptor-like kinase 5 may be important for both the development and progression of PAH. We investigated the therapeutic potential of a well-characterized and potent activin receptor-like kinase 5 inhibitor, SB525334 [6-(2-tert-butyl-5-6-methyl-pyridin-2-yl-1H-imidazol-4-yl)-quinoxaline] for the treatment of PAH. In this study, we demonstrate that pulmonary artery smooth muscle cells from patients with familial forms of idiopathic PAH exhibit heightened sensitivity to TGF-beta1 in vitro, which can be attenuated after the administration of SB525334. We further demonstrate that SB525334 significantly reverses pulmonary arterial pressure and inhibits right ventricular hypertrophy in a rat model of PAH. Immunohistochemical studies confirmed a significant reduction in pulmonary arteriole muscularization induced by monocrotaline (used experimentally to induce PAH) after treatment of rats with SB525334. Collectively, these data are consistent with a role for the activin receptor-like kinase 5 in the progression of idiopathic PAH and imply that strategies to inhibit activin receptor-like kinase 5 signaling may have therapeutic benefit.|*Cell Proliferation/drug effects[MESH]|Animals[MESH]|Blotting, Western[MESH]|Bone Morphogenetic Protein Receptors, Type II/metabolism[MESH]|Disease Models, Animal[MESH]|Disease Progression[MESH]|Enzyme Inhibitors/pharmacology[MESH]|Humans[MESH]|Hypertension, Pulmonary/drug therapy/*enzymology/pathology[MESH]|Hypertrophy, Right Ventricular/drug therapy[MESH]|Image Processing, Computer-Assisted[MESH]|Imidazoles/pharmacology[MESH]|Immunohistochemistry[MESH]|Monocrotaline/toxicity[MESH]|Muscle, Smooth, Vascular/drug effects/*metabolism[MESH]|Protein Serine-Threonine Kinases/drug effects/*metabolism[MESH]|Pulmonary Artery/drug effects/metabolism/pathology[MESH]|Quinoxalines/pharmacology[MESH]|Rats[MESH]|Receptor, Transforming Growth Factor-beta Type I[MESH]|Receptors, Transforming Growth Factor beta/drug effects/*metabolism[MESH]|Reverse Transcriptase Polymerase Chain Reaction[MESH]|Smad3 Protein/metabolism[MESH]|Transforming Growth Factor beta1/metabolism[MESH] |
