Globotriaosylceramide leads to K(Ca)3.1 channel dysfunction: a new insight into endothelial dysfunction in Fabry disease.
OBJECTIVE
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.


RESULTS
The animal model of Fabry disease, α-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.


CONCLUSIONS
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.
Park
Seonghee
S
Department of Physiology, School of Medicine, Ewha Womans University, 911-1 Mok-6-dong, Yang Chun-gu, Seoul 158-710, Republic of Korea.
Kim
Ji Aee
JA
Joo
Ka Young
KY
Choi
Shinkyu
S
Choi
Eun-Nam
EN
Shin
Jung-A
JA
Han
Ki-Hwan
KH
Jung
Sung-Chul
SC
Suh
Suk Hyo
SH
D000818:Animals; D002478:Cells, Cultured; D058546:Class III Phosphatidylinositol 3-Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D000795:Fabry Disease / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D008564:Membrane Potentials; D051379:Mice; D018345:Mice, Knockout; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014281:Trihexosylceramides / Q000378:metabolism*; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology; D000519:alpha-Galactosidase / Q000235:genetics / Q000378:metabolism; D000099229:RE1-Silencing Transcription Factor
D058546:Class III Phosphatidylinositol 3-Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D018129:Phosphatidylinositol Phosphates; D012097:Repressor Proteins; D018808:Transcription Factor AP-1; D014281:Trihexosylceramides; D014665:Vasodilator Agents; D000519:alpha-Galactosidase; D000099229:RE1-Silencing Transcription Factor; C496925:Kcnn4 protein, mouse; C055525:phosphatidylinositol 3-phosphate; C018549:globotriaosylceramide