PMID- 20971723
OWN - NLM
STAT- MEDLINE
DCOM- 20110422
LR  - 20110113
IS  - 1755-3245 (Electronic)
IS  - 0008-6363 (Linking)
VI  - 89
IP  - 2
DP  - 2011 Feb 1
TI  - Globotriaosylceramide leads to K(Ca)3.1 channel dysfunction: a new insight into 
      endothelial dysfunction in Fabry disease.
PG  - 290-9
LID - 10.1093/cvr/cvq333 [doi]
AB  - 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.
FAU - Park, Seonghee
AU  - Park S
AD  - Department of Physiology, School of Medicine, Ewha Womans University, 911-1 
      Mok-6-dong, Yang Chun-gu, Seoul 158-710, Republic of Korea.
FAU - Kim, Ji Aee
AU  - Kim JA
FAU - Joo, Ka Young
AU  - Joo KY
FAU - Choi, Shinkyu
AU  - Choi S
FAU - Choi, Eun-Nam
AU  - Choi EN
FAU - Shin, Jung-A
AU  - Shin JA
FAU - Han, Ki-Hwan
AU  - Han KH
FAU - Jung, Sung-Chul
AU  - Jung SC
FAU - Suh, Suk Hyo
AU  - Suh SH
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20101021
PL  - England
TA  - Cardiovasc Res
JT  - Cardiovascular research
JID - 0077427
RN  - 0 (Intermediate-Conductance Calcium-Activated Potassium Channels)
RN  - 0 (Kcnn4 protein, mouse)
RN  - 0 (Phosphatidylinositol Phosphates)
RN  - 0 (RE1-silencing transcription factor)
RN  - 0 (Repressor Proteins)
RN  - 0 (Transcription Factor AP-1)
RN  - 0 (Trihexosylceramides)
RN  - 0 (Vasodilator Agents)
RN  - 0 (phosphatidylinositol 3-phosphate)
RN  - 71965-57-6 (globotriaosylceramide)
RN  - EC 2.7.1.137 (Class III Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - EC 3.2.1.22 (alpha-Galactosidase)
SB  - IM
CIN - Cardiovasc Res. 2011 Feb 1;89(2):258-9. PMID: 21148146
MH  - Animals
MH  - Cells, Cultured
MH  - Class III Phosphatidylinositol 3-Kinases/metabolism
MH  - Disease Models, Animal
MH  - Dose-Response Relationship, Drug
MH  - Endothelial Cells/drug effects/*metabolism
MH  - Endothelium, Vascular/drug effects/*metabolism/physiopathology
MH  - Extracellular Signal-Regulated MAP Kinases/metabolism
MH  - Fabry Disease/enzymology/genetics/*metabolism/physiopathology
MH  - Intermediate-Conductance Calcium-Activated Potassium Channels/*metabolism
MH  - Membrane Potentials
MH  - Mice
MH  - Mice, Knockout
MH  - Phosphatidylinositol Phosphates/metabolism
MH  - Repressor Proteins/metabolism
MH  - Signal Transduction
MH  - Transcription Factor AP-1/metabolism
MH  - Trihexosylceramides/*metabolism
MH  - Vasodilation
MH  - Vasodilator Agents/pharmacology
MH  - alpha-Galactosidase/genetics/metabolism
EDAT- 2010/10/26 06:00
MHDA- 2011/04/26 06:00
CRDT- 2010/10/26 06:00
PHST- 2010/10/26 06:00 [entrez]
PHST- 2010/10/26 06:00 [pubmed]
PHST- 2011/04/26 06:00 [medline]
AID - cvq333 [pii]
AID - 10.1093/cvr/cvq333 [doi]
PST - ppublish
SO  - Cardiovasc Res. 2011 Feb 1;89(2):290-9. doi: 10.1093/cvr/cvq333. Epub 2010 Oct 
      21.