期刊
CARDIOVASCULAR RESEARCH
卷 89, 期 2, 页码 290-299出版社
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvq333
关键词
alpha-Galactosidase A knockout mice; Endothelial dysfunction; Fabry disease; Globotriaosylceramide; K(Ca)3.1 channel
资金
- Korea Government (MOEHRD) [KRF-2008-041-E00028]
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. KCa3.1 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, KCa3.1 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.
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