Home LiteratureArticle Details
PMID: 18924609 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

ABCG1 and HDL protect against endothelial dysfunction in mice fed a high-cholesterol diet.

The Journal of clinical investigation ·Vol. 118 ·No. 11 ·2008-11-00 ·Pages 3701-13

Terasaka N, Yu S, Yvan-Charvet L, Wang N, Mzhavia N, Langlois R, Pagler T, Li R, Welch CL, Goldberg IJ, Tall AR

Abstract

Plasma HDL levels are inversely related to the incidence of atherosclerotic disease. Some of the atheroprotective effects of HDL are likely mediated via preservation of EC function. Whether the beneficial effects of HDL on ECs depend on its involvement in cholesterol efflux via the ATP-binding cassette transporters ABCA1 and ABCG1, which promote efflux of cholesterol and oxysterols from macrophages, has not been investigated. To address this, we assessed endothelial function in Abca1(-/-), Abcg1(-/-), and Abca1(-/-)Abcg1(-/-) mice fed either a high-cholesterol diet (HCD) or a Western diet (WTD). Non-atherosclerotic arteries from WTD-fed Abcg1(-/-) and Abca1(-/-)Abcg1(-/-) mice exhibited a marked decrease in endothelium-dependent vasorelaxation, while Abca1(-/-) mice had a milder defect. In addition, eNOS activity was reduced in aortic homogenates generated from Abcg1(-/-) mice fed either a HCD or a WTD, and this correlated with decreased levels of the active dimeric form of eNOS. More detailed analysis indicated that ABCG1 was expressed primarily in ECs, and that these cells accumulated the oxysterol 7-ketocholesterol (7-KC) when Abcg1(-/-) mice were fed a WTD. Consistent with these data, ABCG1 had a major role in promoting efflux of cholesterol and 7-KC in cultured human aortic ECs (HAECs). Furthermore, HDL treatment of HAECs prevented 7-KC-induced ROS production and active eNOS dimer disruption in an ABCG1-dependent manner. Our data suggest that ABCG1 and HDL maintain EC function in HCD-fed mice by promoting efflux of cholesterol and 7-oxysterols and preserving active eNOS dimer levels.

MeSH Terms
ATP Binding Cassette Transporter, Subfamily G, Member 1 ATP-Binding Cassette Transporters/genetics,metabolism Animals Cholesterol/metabolism Cholesterol, Dietary/adverse effects Endothelium, Vascular/metabolism Ketocholesterols/metabolism Lipoproteins/genetics,metabolism Lipoproteins, HDL/metabolism Mice Mice, Inbred C57BL Mice, Transgenic Models, Biological Nitric Oxide Synthase Type III/metabolism
Chemicals
ABCG1 protein, mouse ATP Binding Cassette Transporter, Subfamily G, Member 1 ATP-Binding Cassette Transporters Cholesterol, Dietary Ketocholesterols Lipoproteins Lipoproteins, HDL Cholesterol Nitric Oxide Synthase Type III Nos3 protein, mouse 7-ketocholesterol
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Terasaka Naoki
Division of Molecular Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA. [email protected]
Yu Shuiqing
Yvan-Charvet Laurent
Wang Nan
Mzhavia Nino
Langlois Read
Pagler Tamara
Li Rong
Welch Carrie L
Goldberg Ira J
Tall Alan R
References (60)
60 references, click to expand
  1. Reconstituted high-density lipoproteins inhibit the acute pro-oxidant and proinflammatory vascular changes induced by a periarterial collar in normocholesterolemic rabbits.
    Circulation. 2005 Mar 29;111(12):1543-50 PMID: 15781735
  2. Cholesterol oxides in Indian ghee: possible cause of unexplained high risk of atherosclerosis in Indian immigrant populations.
    Lancet. 1987 Sep 19;2(8560):656-8 PMID: 2887943
  3. ABCG1 has a critical role in mediating cholesterol efflux to HDL and preventing cellular lipid accumulation.
    Cell Metab. 2005 Feb;1(2):121-31 PMID: 16054053
  4. ABCG1 redistributes cell cholesterol to domains removable by high density lipoprotein but not by lipid-depleted apolipoproteins.
    J Biol Chem. 2005 Aug 26;280(34):30150-7 PMID: 15994327
  5. Endothelial nitric oxide synthase in vascular disease: from marvel to menace.
    Circulation. 2006 Apr 4;113(13):1708-14 PMID: 16585403
  6. HDL from CETP-deficient subjects shows enhanced ability to promote cholesterol efflux from macrophages in an apoE- and ABCG1-dependent pathway.
    J Clin Invest. 2006 May;116(5):1435-42 PMID: 16670775
  7. Endothelial and antithrombotic actions of HDL.
    Circ Res. 2006 Jun 9;98(11):1352-64 PMID: 16763172
  8. Uncoupling of endothelial nitric oxidase synthase by hypochlorous acid: role of NAD(P)H oxidase-derived superoxide and peroxynitrite.
    Arterioscler Thromb Vasc Biol. 2006 Dec;26(12):2688-95 PMID: 17023679
  9. Molecular regulation of HDL metabolism and function: implications for novel therapies.
    J Clin Invest. 2006 Dec;116(12):3090-100 PMID: 17143322
  10. Inhibition of cholesteryl ester transfer protein by torcetrapib modestly increases macrophage cholesterol efflux to HDL.
    Arterioscler Thromb Vasc Biol. 2007 May;27(5):1132-8 PMID: 17322101
  11. Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women.
    JAMA. 2007 Jul 18;298(3):309-16 PMID: 17635891
  12. Macrophage ABCA1 and ABCG1, but not SR-BI, promote macrophage reverse cholesterol transport in vivo.
    J Clin Invest. 2007 Aug;117(8):2216-24 PMID: 17657311
  13. Apoptosis signal-regulating kinase-1 is involved in vascular endothelial and cardiac remodeling caused by nitric oxide deficiency.
    Hypertension. 2007 Sep;50(3):519-24 PMID: 17646574
  14. Increased endoplasmic reticulum stress in atherosclerotic plaques associated with acute coronary syndrome.
    Circulation. 2007 Sep 11;116(11):1226-33 PMID: 17709641
  15. High-density lipoprotein protects macrophages from oxidized low-density lipoprotein-induced apoptosis by promoting efflux of 7-ketocholesterol via ABCG1.
    Proc Natl Acad Sci U S A. 2007 Sep 18;104(38):15093-8 PMID: 17846428
  16. Spontaneous atherothrombosis and medial degradation in Apoe-/-, Npc1-/- mice.
    Circulation. 2007 Nov 20;116(21):2444-52 PMID: 17984379
  17. Combined deficiency of ABCA1 and ABCG1 promotes foam cell accumulation and accelerates atherosclerosis in mice.
    J Clin Invest. 2007 Dec;117(12):3900-8 PMID: 17992262
  18. SR-BI inhibits ABCG1-stimulated net cholesterol efflux from cells to plasma HDL.
    J Lipid Res. 2008 Jan;49(1):107-14 PMID: 17960026
  19. Cholesterol efflux pathways and other potential mechanisms involved in the athero-protective effect of high density lipoproteins.
    J Intern Med. 2008 Mar;263(3):256-73 PMID: 18271871
  20. HDL, ABC transporters, and cholesterol efflux: implications for the treatment of atherosclerosis.
    Cell Metab. 2008 May;7(5):365-75 PMID: 18460328
  21. Cellular physiology of cholesterol efflux in vascular endothelial cells.
    Circulation. 2004 Nov 2;110(18):2881-8 PMID: 15492319
  22. An excess concentration of oxysterols in the plasma is cytotoxic to cultured endothelial cells.
    Atherosclerosis. 2000 Mar;149(1):191-7 PMID: 10704631
  23. High density lipoprotein prevents oxidized low density lipoprotein-induced inhibition of endothelial nitric-oxide synthase localization and activation in caveolae.
    J Biol Chem. 2000 Apr 14;275(15):11278-83 PMID: 10753938
  24. Protective effect of high density lipoprotein on endothelium-dependent vasodilatation.
    Int J Cardiol. 2000 May 31;73(3):231-6 PMID: 10841964
  25. Inhibition of endothelium-dependent arterial relaxation by oxidized phosphatidylcholine.
    Atherosclerosis. 2000 Sep;152(1):79-87 PMID: 10996342
  26. Specific binding of ApoA-I, enhanced cholesterol efflux, and altered plasma membrane morphology in cells expressing ABC1.
    J Biol Chem. 2000 Oct 20;275(42):33053-8 PMID: 10918065
  27. ABCA1 is the cAMP-inducible apolipoprotein receptor that mediates cholesterol secretion from macrophages.
    J Biol Chem. 2000 Nov 3;275(44):34508-11 PMID: 10918070
  28. NF-kappaB: pivotal mediator or innocent bystander in atherogenesis?
    J Clin Invest. 2001 Feb;107(3):255-64 PMID: 11160146
  29. Mechanisms underlying endothelial dysfunction in diabetes mellitus.
    Circ Res. 2001 Feb 2;88(2):E14-22 PMID: 11157681
  30. High-density lipoprotein binding to scavenger receptor-BI activates endothelial nitric oxide synthase.
    Nat Med. 2001 Jul;7(7):853-7 PMID: 11433352
  31. High-density lipoproteins and endothelial function.
    Circulation. 2001 Oct 16;104(16):1978-83 PMID: 11602504
  32. Oxidation of the zinc-thiolate complex and uncoupling of endothelial nitric oxide synthase by peroxynitrite.
    J Clin Invest. 2002 Mar;109(6):817-26 PMID: 11901190
  33. A novel mechanism for the beneficial vascular effects of high-density lipoprotein cholesterol: enhanced vasorelaxation and increased endothelial nitric oxide synthase expression.
    Am Heart J. 2002 Jul;144(1):165-72 PMID: 12094204
  34. HDL counterbalance the proinflammatory effect of oxidized LDL by inhibiting intracellular reactive oxygen species rise, proteasome activation, and subsequent NF-kappaB activation in smooth muscle cells.
    FASEB J. 2003 Apr;17(6):743-5 PMID: 12586748
  35. HDL-associated estradiol stimulates endothelial NO synthase and vasodilation in an SR-BI-dependent manner.
    J Clin Invest. 2003 May;111(10):1579-87 PMID: 12750408
  36. Restoration of endothelial function by increasing high-density lipoprotein in subjects with isolated low high-density lipoprotein.
    Circulation. 2003 Jun 17;107(23):2944-8 PMID: 12771001
  37. Relation between high-density lipoprotein cholesterol and peripheral vasomotor function.
    Am J Cardiol. 2003 Aug 1;92(3):275-9 PMID: 12888130
  38. HDL induces NO-dependent vasorelaxation via the lysophospholipid receptor S1P3.
    J Clin Invest. 2004 Feb;113(4):569-81 PMID: 14966566
  39. Selective attenuation of endothelium-mediated vasodilation in atherosclerotic human coronary arteries.
    Circ Res. 1988 Feb;62(2):185-90 PMID: 2448055
  40. Quantification of oxysterols in Dutch foods: egg products and mixed diets.
    Lipids. 1988 Nov;23(11):1079-85 PMID: 3237009
  41. Impaired endothelium-dependent relaxation to aggregating platelets and related vasoactive substances in porcine coronary arteries in hypercholesterolemia and atherosclerosis.
    Circ Res. 1989 May;64(5):900-14 PMID: 2495869
  42. High-density lipoprotein--the clinical implications of recent studies.
    N Engl J Med. 1989 Nov 9;321(19):1311-6 PMID: 2677733
  43. Diet-induced atherosclerosis increases the release of nitrogen oxides from rabbit aorta.
    J Clin Invest. 1990 Dec;86(6):2109-16 PMID: 2254462
  44. Expression of human apolipoprotein A-I in transgenic mice results in reduced plasma levels of murine apolipoprotein A-I and the appearance of two new high density lipoprotein size subclasses.
    Proc Natl Acad Sci U S A. 1991 Jan 15;88(2):434-8 PMID: 1703299
  45. Modulation of coronary vasomotor tone in humans. Progressive endothelial dysfunction with different early stages of coronary atherosclerosis.
    Circulation. 1991 Feb;83(2):391-401 PMID: 1991363
  46. Coronary atherosclerotic wall thickening and vascular reactivity in humans. Elevated high-density lipoprotein levels ameliorate abnormal vasoconstriction in early atherosclerosis.
    Circulation. 1994 Jun;89(6):2525-32 PMID: 8205660
  47. Inhibitors of arterial relaxation among components of human oxidized low-density lipoproteins. Cholesterol derivatives oxidized in position 7 are potent inhibitors of endothelium-dependent relaxation.
    Circulation. 1997 Feb 4;95(3):723-31 PMID: 9024163
  48. Effect of a single high-fat meal on endothelial function in healthy subjects.
    Am J Cardiol. 1997 Feb 1;79(3):350-4 PMID: 9036757
  49. Structural identification by mass spectrometry of oxidized phospholipids in minimally oxidized low density lipoprotein that induce monocyte/endothelial interactions and evidence for their presence in vivo.
    J Biol Chem. 1997 May 23;272(21):13597-607 PMID: 9153208
  50. Endothelial nitric oxide synthase: modulations of the distal heme site produced by progressive N-terminal deletions.
    Biochemistry. 1997 Jul 15;36(28):8530-8 PMID: 9214298
  51. Inhibition by cholesterol oxides of NO release from human vascular endothelial cells.
    Arterioscler Thromb Vasc Biol. 1998 Jul;18(7):1054-60 PMID: 9672065
  52. Dietary oxysterols are incorporated in plasma triglyceride-rich lipoproteins, increase their susceptibility to oxidation and increase aortic cholesterol concentration of rabbits.
    J Lipid Res. 1998 Oct;39(10):1995-2004 PMID: 9788246
  53. Oxysterols and atherosclerosis.
    Atherosclerosis. 1999 Jan;142(1):1-28 PMID: 9920502
  54. Impairment of endothelium-dependent arterial relaxation by high-fat feeding in ApoE-deficient mice: toward normalization by human ApoA-I expression.
    Circulation. 1999 Sep 14;100(11):1230-5 PMID: 10484545
  55. The oxidation hypothesis of atherogenesis: the role of oxidized phospholipids and HDL.
    J Lipid Res. 2004 Jun;45(6):993-1007 PMID: 15060092
  56. High density lipoproteins in the intersection of diabetes mellitus, inflammation and cardiovascular disease.
    Curr Opin Lipidol. 2004 Jun;15(3):269-78 PMID: 15166782
  57. HDL cholesterol and protective factors in atherosclerosis.
    Circulation. 2004 Jun 15;109(23 Suppl 1):III8-14 PMID: 15198960
  58. ATP-binding cassette transporters G1 and G4 mediate cellular cholesterol efflux to high-density lipoproteins.
    Proc Natl Acad Sci U S A. 2004 Jun 29;101(26):9774-9 PMID: 15210959
  59. Impaired muscarinic endothelium-dependent relaxation and cyclic guanosine 5'-monophosphate formation in atherosclerotic human coronary artery and rabbit aorta.
    J Clin Invest. 1987 Jan;79(1):170-4 PMID: 2432088
  60. Diabetes induces endothelial dysfunction but does not increase neointimal formation in high-fat diet fed C57BL/6J mice.
    Circ Res. 2005 Jun 10;96(11):1178-84 PMID: 15879311
Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI35470
Email
[email protected]
Published
2008-11-00
Epub
2008-00-16
Pages
3701-13
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC2567835
Subset
IM
Grants
NHLBI NIH HHS · P01 HL054591 · United States
NHLBI NIH HHS · HL54591 · United States
External Links
PubMed source DOI: 10.1172/JCI35470 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2