PMID- 24158513
OWN - NLM
STAT- MEDLINE
DCOM- 20140218
LR  - 20131216
IS  - 1524-4636 (Electronic)
IS  - 1079-5642 (Linking)
VI  - 34
IP  - 1
DP  - 2014 Jan
TI  - Globotriaosylceramide induces lysosomal degradation of endothelial KCa3.1 in 
      fabry disease.
PG  - 81-9
LID - 10.1161/ATVBAHA.113.302200 [doi]
AB  - OBJECTIVE: Globotriaosylceramide (Gb3) induces KCa3.1 downregulation in Fabry 
      disease (FD). We investigated whether Gb3 induces KCa3.1 endocytosis and 
      degradation. APPROACH AND RESULTS: KCa3.1, especially plasma membrane-localized 
      KCa3.1, was downregulated in both Gb3-treated mouse aortic endothelial cells 
      (MAECs) and human umbilical vein endothelial cells. Gb3-induced KCa3.1 
      downregulation was prevented by lysosomal inhibitors but not by a proteosomal 
      inhibitor. Endoplasmic reticulum stress-inducing agents did not induce KCa3.1 
      downregulation. Gb3 upregulated the protein levels of early endosome antigen 1 
      and lysosomal-associated membrane protein 2 in MAECs. Compared with MAECs from 
      age-matched wild-type mice, those from aged alpha-galactosidase A (Gla)-knockout 
      mice, an animal model of FD, showed downregulated KCa3.1 expression and 
      upregulated early endosome antigen 1 and lysosomal-associated membrane protein 2 
      expression. In contrast, no significant difference was found in early endosome 
      antigen 1 and lysosomal-associated membrane protein 2 expression between young 
      Gla-knockout and wild-type MAECs. In aged Gla-knockout MAECs, clathrin was 
      translocated close to the cell border and clathrin knockdown recovered KCa3.1 
      expression. Rab5, an effector of early endosome antigen 1, was upregulated, and 
      Rab5 knockdown restored KCa3.1 expression, the current, and endothelium-dependent 
      relaxation. CONCLUSIONS: -Gb3 accelerates the endocytosis and lysosomal 
      degradation of endothelial KCa3.1 via a clathrin-dependent process, leading to 
      endothelial dysfunction in FD.
FAU - Choi, Shinkyu
AU  - Choi S
AD  - From the Departments of Physiology (S.C., J.A.K., H.-Y.N., S.-E.C., S.P., S.H.S.) 
      and Biochemistry (S.-C.J.), Medical School, Ewha Womans University, Seoul, Korea.
FAU - Kim, Ji Aee
AU  - Kim JA
FAU - Na, Hye-Young
AU  - Na HY
FAU - Cho, Sung-Eun
AU  - Cho SE
FAU - Park, Seonghee
AU  - Park S
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 - 20131024
PL  - United States
TA  - Arterioscler Thromb Vasc Biol
JT  - Arteriosclerosis, thrombosis, and vascular biology
JID - 9505803
RN  - 0 (Clathrin)
RN  - 0 (Intermediate-Conductance Calcium-Activated Potassium Channels)
RN  - 0 (KCNN4 protein, human)
RN  - 0 (Kcnn4 protein, mouse)
RN  - 0 (LAMP2 protein, human)
RN  - 0 (Lysosomal-Associated Membrane Protein 2)
RN  - 0 (Trihexosylceramides)
RN  - 0 (Vesicular Transport Proteins)
RN  - 0 (early endosome antigen 1)
RN  - 71965-57-6 (globotriaosylceramide)
RN  - EC 3.2.1.22 (alpha-Galactosidase)
RN  - EC 3.6.5.2 (rab5 GTP-Binding Proteins)
SB  - IM
CIN - Arterioscler Thromb Vasc Biol. 2014 Jan;34(1):2-4. PMID: 24335674
MH  - Animals
MH  - Cells, Cultured
MH  - Clathrin/genetics/metabolism
MH  - Disease Models, Animal
MH  - Endocytosis
MH  - Endothelial Cells/*enzymology
MH  - Endothelium, Vascular/*enzymology/physiopathology
MH  - Fabry Disease/*enzymology/genetics/physiopathology
MH  - Human Umbilical Vein Endothelial Cells/enzymology
MH  - Humans
MH  - Intermediate-Conductance Calcium-Activated Potassium Channels/*metabolism
MH  - Lysosomal-Associated Membrane Protein 2/metabolism
MH  - Lysosomes/*metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - Protein Transport
MH  - Proteolysis
MH  - RNA Interference
MH  - Transfection
MH  - Trihexosylceramides/*metabolism
MH  - Vasodilation
MH  - Vesicular Transport Proteins/metabolism
MH  - alpha-Galactosidase/genetics/metabolism
MH  - rab5 GTP-Binding Proteins/genetics/metabolism
OTO - NOTNLM
OT  - Ca2+-activated K+ channels
OT  - Fabry disease
OT  - glycosphingolipids
OT  - protein transport
EDAT- 2013/10/26 06:00
MHDA- 2014/02/19 06:00
CRDT- 2013/10/26 06:00
PHST- 2013/10/26 06:00 [entrez]
PHST- 2013/10/26 06:00 [pubmed]
PHST- 2014/02/19 06:00 [medline]
AID - ATVBAHA.113.302200 [pii]
AID - 10.1161/ATVBAHA.113.302200 [doi]
PST - ppublish
SO  - Arterioscler Thromb Vasc Biol. 2014 Jan;34(1):81-9. doi: 
      10.1161/ATVBAHA.113.302200. Epub 2013 Oct 24.