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

Seonghee Park1, Ji Aee Kim, Ka Young Joo

  • 1Department of Physiology, School of Medicine, Ewha Womans University, 911-1 Mok-6-dong, Yang Chun-gu, Seoul 158-710, Republic of Korea.

Cardiovascular Research
|October 26, 2010
PubMed

Insights

Globotriaosylceramide (Gb3) accumulation in Fabry disease impairs K(Ca)3.1 channels, reducing endothelial relaxation. This dysfunction stems from altered signaling pathways and lipid levels, contributing to vascular disease.

Area of Science:

  • Cardiovascular Biology
  • Cell Physiology
  • Genetic Diseases

Background:

  • Endothelial globotriaosylceramide (Gb3) accumulation is linked to endothelial dysfunction in Fabry disease.
  • K(Ca)3.1 channels are crucial for endothelium-dependent relaxation.

Purpose of the Study:

  • To investigate the impact of Gb3 on K(Ca)3.1 channels in endothelial cells.
  • To elucidate the mechanisms underlying Gb3-induced endothelial dysfunction.

Main Methods:

  • Utilized α-galactosidase A (Gla) knockout mice as a model for Fabry disease.
  • Assessed K(Ca)3.1 channel function and expression in mouse aortic endothelial cells (MAECs).
  • Examined the effects of Gb3 treatment on MAECs and mouse aortic rings.

Main Results:

  • Aged Gla knockout mice showed age-dependent K(Ca)3.1 channel dysfunction, with reduced current and expression in MAECs.
  • Gb3 treatment reduced K(Ca)3.1 channel current and expression in MAECs.
  • Gb3 accumulation altered signaling pathways (ERK, AP-1, REST) and phosphatidylinositol 3-phosphate [PI(3)P] levels, impairing endothelium-dependent relaxation.

Conclusions:

  • Gb3 accumulation reduces K(Ca)3.1 channel expression and activity through specific molecular mechanisms.
  • K(Ca)3.1 channel dysfunction in vascular endothelial cells likely contributes to Fabry disease vasculopathy.
Abstract

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