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Cholesterol depletion impairs vascular reactivity to endothelin-1 by reducing store-operated Ca2+ entry dependent on TRPC1.

Bergdahl, Andreas LU ; Gomez, Maria LU ; Dreja, Karl LU ; Xu, Shang-Zhong; Adner, Mikael LU ; Beech, David J; Broman, Jonas LU ; Hellstrand, Per LU and Swärd, Karl LU (2003) In Circulation Research 93(9). p.839-847
Abstract
The reactivity of the vascular wall to endothelin-1 (ET-1) is influenced by cholesterol, which is of possible importance for the progression of atherosclerosis. To elucidate signaling steps affected, the cholesterol acceptor methyl-ß-cyclodextrin (mßcd, 10 mmol/L) was used to manipulate membrane cholesterol and disrupt caveolae in intact rat arteries. In endothelium-denuded caudal artery, contractile responsiveness to 10 nmol/L ET-1 (mediated by the ETA receptor) was reduced by mßcd and increased by cholesterol. Neither ligand binding nor colocalization of ETA and caveolin-1 was affected by mßcd. Ca2+ inflow via store-operated channels after depletion of intracellular Ca2+ stores was reduced in mßcd-treated caudal arteries, as shown by... (More)
The reactivity of the vascular wall to endothelin-1 (ET-1) is influenced by cholesterol, which is of possible importance for the progression of atherosclerosis. To elucidate signaling steps affected, the cholesterol acceptor methyl-ß-cyclodextrin (mßcd, 10 mmol/L) was used to manipulate membrane cholesterol and disrupt caveolae in intact rat arteries. In endothelium-denuded caudal artery, contractile responsiveness to 10 nmol/L ET-1 (mediated by the ETA receptor) was reduced by mßcd and increased by cholesterol. Neither ligand binding nor colocalization of ETA and caveolin-1 was affected by mßcd. Ca2+ inflow via store-operated channels after depletion of intracellular Ca2+ stores was reduced in mßcd-treated caudal arteries, as shown by Mn2+ quench rate and intracellular [Ca2+] response. Expression of TRPC1, 3, and 6 was detected by reverse transcriptase–polymerase chain reaction, and colocalization of TRPC1 with caveolin-1 was reduced by mßcd, as seen by immunofluorescence. Part of the contractile response to ET-1 was inhibited by Ni2+ (0.5 mmol/L) and by a TRPC1 blocking antibody. In the basilar artery, exhibiting less store-operated channel activity than the caudal artery, ET-1–induced contractions were insensitive to the TRPC1 blocking antibody and to mßcd. Increased store-operated channel activity in basilar arteries after organ culture correlated with increased sensitivity of ET-1 contraction to mßcd. These results suggest that cholesterol influences vascular reactivity to ET-1 by affecting the caveolar localization of TRPC1. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
methyl-ß-cyclodextrin, arterial smooth muscle, endothelin, caveolae, store-operated Ca2+ channels
in
Circulation Research
volume
93
issue
9
pages
839 - 847
publisher
American Heart Association
external identifiers
  • pmid:14551243
  • wos:000186273800009
  • scopus:0242298630
ISSN
0009-7330
DOI
language
English
LU publication?
yes
id
a10cb42a-fd3a-41da-85c3-8bcf216946eb (old id 118291)
date added to LUP
2007-07-10 11:46:11
date last changed
2018-05-29 11:14:00
@article{a10cb42a-fd3a-41da-85c3-8bcf216946eb,
  abstract     = {The reactivity of the vascular wall to endothelin-1 (ET-1) is influenced by cholesterol, which is of possible importance for the progression of atherosclerosis. To elucidate signaling steps affected, the cholesterol acceptor methyl-ß-cyclodextrin (mßcd, 10 mmol/L) was used to manipulate membrane cholesterol and disrupt caveolae in intact rat arteries. In endothelium-denuded caudal artery, contractile responsiveness to 10 nmol/L ET-1 (mediated by the ETA receptor) was reduced by mßcd and increased by cholesterol. Neither ligand binding nor colocalization of ETA and caveolin-1 was affected by mßcd. Ca2+ inflow via store-operated channels after depletion of intracellular Ca2+ stores was reduced in mßcd-treated caudal arteries, as shown by Mn2+ quench rate and intracellular [Ca2+] response. Expression of TRPC1, 3, and 6 was detected by reverse transcriptase–polymerase chain reaction, and colocalization of TRPC1 with caveolin-1 was reduced by mßcd, as seen by immunofluorescence. Part of the contractile response to ET-1 was inhibited by Ni2+ (0.5 mmol/L) and by a TRPC1 blocking antibody. In the basilar artery, exhibiting less store-operated channel activity than the caudal artery, ET-1–induced contractions were insensitive to the TRPC1 blocking antibody and to mßcd. Increased store-operated channel activity in basilar arteries after organ culture correlated with increased sensitivity of ET-1 contraction to mßcd. These results suggest that cholesterol influences vascular reactivity to ET-1 by affecting the caveolar localization of TRPC1.},
  author       = {Bergdahl, Andreas and Gomez, Maria and Dreja, Karl and Xu, Shang-Zhong and Adner, Mikael and Beech, David J and Broman, Jonas and Hellstrand, Per and Swärd, Karl},
  issn         = {0009-7330},
  keyword      = {methyl-ß-cyclodextrin,arterial smooth muscle,endothelin,caveolae,store-operated Ca2+ channels},
  language     = {eng},
  number       = {9},
  pages        = {839--847},
  publisher    = {American Heart Association},
  series       = {Circulation Research},
  title        = {Cholesterol depletion impairs vascular reactivity to endothelin-1 by reducing store-operated Ca2+ entry dependent on TRPC1.},
  url          = {http://dx.doi.org/},
  volume       = {93},
  year         = {2003},
}