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10.1093/cvr/cvq333 http://scihub22266oqcxt.onion/10.1093/cvr/cvq333 20971723!ä!20971723 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 267.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 267.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 267.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534       Cardiovasc+Res 2011 ; 89 (2): 290-9 Nephropedia Template TP {{tp|p=20971723|t=2011. Globotriaosylceramide leads to K(Ca)3 1 channel dysfunction: a new insight into endothelial dysfunction in Fabry disease |pdf=|usr=}}{{20971723}} gab.com Text Globotriaosylceramide leads to K(Ca)3 1 channel dysfunction: a new insight into endothelial dysfunction in Fabry disease JO: Cardiovasc Res http://www.kidney.de/pget.php?&tw=1&pmid=20971723 #FOAvip AIMS: Excessive endothelial globotriaosylceramide (Gb3) accumulation is associated with endothelial dysfunction and impaired endothelium-dependent relaxation in Fabry disease. In endothelial cells, K(Ca)3.1 channels contribute to endothelium-dependent relaxation. However, the effect of Gb3 on K(Ca)3.1 channels and the underlying mechanisms of Gb3-induced dysfunction are unknown. Herein, we hypothesized that Gb3 accumulation induces K(Ca)3.1 channel dysfunction and aimed to clarify the underlying mechanisms. METHODS AND RESULTS: The animal model of Fabry disease, alpha-galactosidase A (Gla) knockout mice, displayed age-dependent K(Ca)3.1 channel dysfunction. K(Ca)3.1 current and the channel expression were significantly reduced in mouse aortic endothelial cells (MAECs) of aged Gla knockout mice, whereas they were not changed in MAECs of wild-type and young Gla knockout mice. In addition, K(Ca)3.1 current and the channel expression were concentration-dependently reduced in Gb3-treated MAECs. In both Gb3-treated and aged Gla knockout MAECs, extracellular signal-regulated kinase (ERK) and activator protein-1 (AP-1) were down-regulated and repressor element-1 silencing transcription factor (REST) was up-regulated. Gb3 inhibited class III phosphoinositide 3-kinase and decreased intracellular levels of phosphatidylinositol 3-phosphate [PI(3)P]. In addition, endothelium-dependent relaxation was significantly attenuated in Gb3-treated mouse aortic rings. CONCLUSION: Gb3 accumulation reduces K(Ca)3.1 channel expression by down-regulating ERK and AP-1 and up-regulating REST and the channel activity by decreasing intracellular levels of PI(3)P. Gb3 thereby evokes K(Ca)3.1 channel dysfunction, and the channel dysfunction in vascular endothelial cells may contribute to vasculopathy in Fabry disease. Twit Text FOAVip Globotriaosylceramide leads to K(Ca)3 1 channel dysfunction: a new insight into endothelial dysfunction in Fabry disease ????Cardiovasc Res http://www.kidney.de/pget.php?&tw=1&pmid=20971723 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=20971723 #FOAvip English Wikipedia <ref>{{Cite pmid|20971723}}</ref> Globotriaosylceramide leads to K(Ca)3 1 channel dysfunction: a new insight into endothelial dysfunction in Fabry disease #MMPMID20971723 Park S; Kim JA; Joo KY; Choi S; Choi EN; Shin JA; Han KH; Jung SC; Suh SH Cardiovasc Res 2011[Feb]; 89 (2): 290-9 PMID20971723show ga AIMS: Excessive endothelial globotriaosylceramide (Gb3) accumulation is associated with endothelial dysfunction and impaired endothelium-dependent relaxation in Fabry disease. In endothelial cells, K(Ca)3.1 channels contribute to endothelium-dependent relaxation. However, the effect of Gb3 on K(Ca)3.1 channels and the underlying mechanisms of Gb3-induced dysfunction are unknown. Herein, we hypothesized that Gb3 accumulation induces K(Ca)3.1 channel dysfunction and aimed to clarify the underlying mechanisms. METHODS AND RESULTS: The animal model of Fabry disease, alpha-galactosidase A (Gla) knockout mice, displayed age-dependent K(Ca)3.1 channel dysfunction. K(Ca)3.1 current and the channel expression were significantly reduced in mouse aortic endothelial cells (MAECs) of aged Gla knockout mice, whereas they were not changed in MAECs of wild-type and young Gla knockout mice. In addition, K(Ca)3.1 current and the channel expression were concentration-dependently reduced in Gb3-treated MAECs. In both Gb3-treated and aged Gla knockout MAECs, extracellular signal-regulated kinase (ERK) and activator protein-1 (AP-1) were down-regulated and repressor element-1 silencing transcription factor (REST) was up-regulated. Gb3 inhibited class III phosphoinositide 3-kinase and decreased intracellular levels of phosphatidylinositol 3-phosphate [PI(3)P]. In addition, endothelium-dependent relaxation was significantly attenuated in Gb3-treated mouse aortic rings. CONCLUSION: Gb3 accumulation reduces K(Ca)3.1 channel expression by down-regulating ERK and AP-1 and up-regulating REST and the channel activity by decreasing intracellular levels of PI(3)P. Gb3 thereby evokes K(Ca)3.1 channel dysfunction, and the channel dysfunction in vascular endothelial cells may contribute to vasculopathy in Fabry disease. |Animals[MESH] |Cells, Cultured[MESH] |Class III Phosphatidylinositol 3-Kinases/metabolism[MESH] |Disease Models, Animal[MESH] |Dose-Response Relationship, Drug[MESH] |Endothelial Cells/drug effects/*metabolism[MESH] |Endothelium, Vascular/drug effects/*metabolism/physiopathology[MESH] |Extracellular Signal-Regulated MAP Kinases/metabolism[MESH] |Fabry Disease/enzymology/genetics/*metabolism/physiopathology[MESH] |Intermediate-Conductance Calcium-Activated Potassium Channels/*metabolism[MESH] |Membrane Potentials[MESH] |Mice[MESH] |Mice, Knockout[MESH] |Phosphatidylinositol Phosphates/metabolism[MESH] |Repressor Proteins/metabolism[MESH] |Signal Transduction[MESH] |Transcription Factor AP-1/metabolism[MESH] |Trihexosylceramides/*metabolism[MESH] |Vasodilation[MESH] |Vasodilator Agents/pharmacology[MESH]Globotriaosylceramide leads to K(Ca)3 1 channel dysfunction: a new ins(epmc).pdf DeepDyve Pubget Overpricing