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10.1074/jbc.M113.458729 http://scihub22266oqcxt.onion/10.1074/jbc.M113.458729 C3675591!3675591 !23612967     free     free     free Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=23612967 &cmd=llinks): Failed to open stream: HTTP request failed! 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A molecular mechanism for therapeutic effects of cGMP-elevating agents in pulmonary arterial hypertension |pdf=|usr=}}{{23612967 }} gab.com Text A molecular mechanism for therapeutic effects of cGMP-elevating agents in pulmonary arterial hypertension JO: J Biol Chem http://www.kidney.de/pget.php?&tw=1&pmid=23612967 #FOAvip Pulmonary arterial hypertension (PAH) is a progressive, usually fatal disease with abnormal vascular remodeling. Pulmonary artery smooth muscle cells (PASMCs) from PAH patients are hyperproliferative and apoptosis-resistant and demonstrate decreased signaling in response to bone morphogenetic proteins (BMPs). Cyclic GMP-elevating agents are beneficial in PAH, but their mechanism(s) of action are incompletely understood. Here we show that BMP signaling via Smad1/5/8 requires cGMP-dependent protein kinase isotype I (PKGI) to maintain PASMCs in a differentiated, low proliferative state. BMP cooperation with cGMP/PKGI was crucial for transcription of contractile genes and suppression of pro-proliferative and anti-apoptotic genes. Lungs from mice with low or absent PKGI (Prkg1(+/-) and Prkg1(-/-) mice) exhibited impaired BMP signaling, decreased contractile gene expression, and abnormal vascular remodeling. Conversely, cGMP stimulation of PKGI restored defective BMP signaling in rats with hypoxia-induced PAH, consistent with cGMP-elevating agents reversing vascular remodeling in this PAH model. Our results provide a mechanism for the therapeutic effects of cGMP-elevating agents in PAH and suggest that combining them with BMP mimetics may provide a novel, disease-modifying approach to PAH therapy. Twit Text FOAVip A molecular mechanism for therapeutic effects of cGMP-elevating agents in pulmonary arterial hypertension ????J Biol Chem http://www.kidney.de/pget.php?&tw=1&pmid=23612967 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=23612967 #FOAvip English Wikipedia <ref>{{Cite pmid|23612967 }}</ref> A molecular mechanism for therapeutic effects of cGMP-elevating agents in pulmonary arterial hypertension #MMPMID23612967 Schwappacher R ; Kilic A ; Kojonazarov B ; Lang M ; Diep T ; Zhuang S ; Gawlowski T ; Schermuly RT ; Pfeifer A ; Boss GR ; Pilz RB J Biol Chem 2013[Jun]; 288 (23 ): 16557-16566 PMID23612967 show ga Pulmonary arterial hypertension (PAH) is a progressive, usually fatal disease with abnormal vascular remodeling. Pulmonary artery smooth muscle cells (PASMCs) from PAH patients are hyperproliferative and apoptosis-resistant and demonstrate decreased signaling in response to bone morphogenetic proteins (BMPs). Cyclic GMP-elevating agents are beneficial in PAH, but their mechanism(s) of action are incompletely understood. Here we show that BMP signaling via Smad1/5/8 requires cGMP-dependent protein kinase isotype I (PKGI) to maintain PASMCs in a differentiated, low proliferative state. BMP cooperation with cGMP/PKGI was crucial for transcription of contractile genes and suppression of pro-proliferative and anti-apoptotic genes. Lungs from mice with low or absent PKGI (Prkg1(+/-) and Prkg1(-/-) mice) exhibited impaired BMP signaling, decreased contractile gene expression, and abnormal vascular remodeling. Conversely, cGMP stimulation of PKGI restored defective BMP signaling in rats with hypoxia-induced PAH, consistent with cGMP-elevating agents reversing vascular remodeling in this PAH model. Our results provide a mechanism for the therapeutic effects of cGMP-elevating agents in PAH and suggest that combining them with BMP mimetics may provide a novel, disease-modifying approach to PAH therapy. |Animals [MESH] |Cell Line, Transformed [MESH] |Cyclic GMP-Dependent Protein Kinase Type I/genetics/metabolism [MESH] |Cyclic GMP/genetics/*metabolism [MESH] |Humans [MESH] |Hypertension, Pulmonary/drug therapy/genetics/*metabolism/pathology [MESH] |Matrix Metalloproteinases, Secreted/genetics/metabolism [MESH] |Mice [MESH] |Mice, Knockout [MESH] |Muscle, Smooth, Vascular/*metabolism/pathology [MESH] |Myocytes, Smooth Muscle/*metabolism/pathology [MESH] |Rats [MESH] |Signal Transduction/genetics [MESH]A molecular mechanism for therapeutic effects of cGMP-elevating agents(epmc).pdf DeepDyve Pubget Overpricing