Cellular Cholesterol Efflux Mediated by Cyclodextrins

Kilsdonk, Elisabeth P.C.; Yancey, Patricia G.; Stoudt, Genevieve; Bangerter, Faan Wen; Johnson, W. J.; Phillips, Michael C.; Rothblat, George H.

doi:10.1074/jbc.270.29.17250

Cited by 756 publications

(615 citation statements)

References 36 publications

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“…Caveolae are small membrane invaginations, rich in cholesterol, involved in signal transduction by ensuring the compartmentalization of several signaling proteins (Doyle et al, 1997;Oh and Schnitzer, 2001;Liu et al, 2002). Cyclodextrin, a water-soluble cyclic oligosaccharide formed of seven glucopyranose units able to accept one molecule of cholesterol in its hydrophobic core, is a membrane-impermeable molecule that depletes cellular cholesterol content through solubilization of the plasmalemmal cholesterol (Kilsdonk et al, 1995). This cholesterol-binding agent has been efficiently used as a pharmacological tool to study the role of caveolae in vascular reactivity (Dreja et al, 2002;Kaiser et al, 2002;Je et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Dynamic Association of Nitric Oxide Downstream Signaling Molecules with Endothelial Caveolin-1 in Rat Aorta

Linder¹,

McCluskey²,

Cole³

et al. 2005

J Pharmacol Exp Ther

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Classically, nitric oxide (NO) formed by endothelial NO synthase (eNOS) freely diffuses from its generation site to smooth muscle cells where it activates soluble guanylyl cyclase (sGC), producing cGMP. Subsequently, cGMP activates both cGMPand cAMP-dependent protein kinases [cGMP-dependent protein kinase (PKG) and cAMP-dependent protein kinase (PKA), respectively], leading to smooth muscle relaxation. In endothelial cells, eNOS has been localized to caveolae, small invaginations of the plasma membrane rich in cholesterol. Membrane cholesterol depletion impairs acetylcholine (ACh)-induced relaxation due to alteration in caveolar structure. Given the nature of NO to be more soluble in a hydrophobic environment than in water, and assuming that colocalization of components in a signal transduction cascade seems to be a critical determinant of signaling efficiency by eNOS activation, we hypothesize that sGC, PKA, and PKG activation may occur at the plasma membrane caveolae. In endothelium-intact rat aortic rings, the relaxation induced by ACh, by the sGC activator 3-(5Ј-hydroxymethyl-2Јfuryl)-1-benzyl indazole (YC-1), and by 8-bromocGMP was impaired in the presence of methyl-␤-cyclodextrin, a drug that disassembles caveolae by sequestering cholesterol from the membrane. sGC, PKG, and PKA were colocalized with caveolin-1 in aortic endothelium, and this colocalization was abolished by methyl-␤-cyclodextrin. Methyl-␤-cyclodextrin efficiently disassembled caveolae in endothelium. In summary, our results provide evidence of compartmentalization of sGC, PKG, and PKA in endothelial caveolae contributing to NO signaling cascade, giving new insights by which the endothelium mediates vascular smooth muscle relaxation.

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Section: Discussionmentioning

confidence: 99%

Dynamic Association of Nitric Oxide Downstream Signaling Molecules with Endothelial Caveolin-1 in Rat Aorta

Linder¹,

McCluskey²,

Cole³

et al. 2005

J Pharmacol Exp Ther

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“…The cholesterol content of CHO cell membranes was modulated by preincubation of cells with cyclodextrin (5.0 mM, 2 h) [22]. Cells were then analyzed for transfer of rePON1 by Western blotting, as described above.…”

Section: Cyclodextrin Treatment Of Cellsmentioning

confidence: 99%

HDL-associated paraoxonase-1 can redistribute to cell membranes and influence sensitivity to oxidative stress

Deakin

Bioletto

Bochaton‐Piallat

et al. 2011

Free Radical Biology and Medicine

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a b s t r a c t a r t i c l e i n f oParaoxonase-1 (PON1) is a high-density lipoprotein (HDL)-associated serum enzyme thought to make a major contribution to the antioxidant capacity of the lipoprotein. In previous studies, we proposed that HDL promoted PON1 secretion by transfer of the enzyme from its plasma membrane location to HDL transiently anchored to the hepatocyte. This study examined whether PON1 can be transferred into cell membranes and retain its enzymatic activities and functions. Using Chinese hamster ovary and human endothelial cells, we found that recombinant PON1 as well as PON1 associated with purified human HDL was freely exchanged between the external medium and the cell membranes. Transferred PON1 was located in the external face of the plasma membrane of the cells in an enzymatically active form. The transfer of PON1 led to a gain of function by the target cells, as revealed by significantly reduced susceptibility to oxidative stress and significantly increased ability to neutralize the bacterial virulence agent 3-oxo-C 12 -homoserine lactone. The data demonstrate that PON1 is not a fixed component of HDL and suggest that the enzyme could also exert its protective functions outside the lipoprotein environment. The observations may be of relevance to tissues exposed to oxidative stress and/or bacterial infection.

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“…Methyl-β-cyclodextrin is a well established tool that selectively and quickly extracts cholesterol from plasma membranes in preference to other lipids [19]. These treatments reduce intracellular cholesterol without affecting cell viability within the time window selected for the experiments.…”

Section: Cholesterol Depletionmentioning

confidence: 99%

Distinct modes of molecular regulation of CCL3 induced calcium flux in monocytic cells

Cardaba

Müeller

2009

Biochemical Pharmacology

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Page 1 of 32A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 by MCD addition, which shows that the cholesterol content in the membrane is only one factor in determining the amount of receptor response. We show that CCR5signalling is dependant on thapsigargin-sensitive Ca 2+ stores and on activation of ryanodine receptors as well as InsP3 receptors or store-operated channels.Cholesterol depletion with MCD changes the thapsigargin sensitivity in THP-1 cells * ManuscriptPage 2 of 32 A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 2 and also alters receptor-G-protein coupling towards pertussis toxin (PTX) independent G-proteins. Cholesterol removal by MCD in THP-1 cells has far reaching consequences for receptor activation and signalling and emphasises the need for a clearer understanding of how membrane fluidity affects receptor signalling events.

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Cellular Cholesterol Efflux Mediated by Cyclodextrins

Cited by 756 publications

References 36 publications

Dynamic Association of Nitric Oxide Downstream Signaling Molecules with Endothelial Caveolin-1 in Rat Aorta

Dynamic Association of Nitric Oxide Downstream Signaling Molecules with Endothelial Caveolin-1 in Rat Aorta

HDL-associated paraoxonase-1 can redistribute to cell membranes and influence sensitivity to oxidative stress

Distinct modes of molecular regulation of CCL3 induced calcium flux in monocytic cells

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