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Cited by 114Cholesterol and Lipid MetabolismAtherosclerosis and Cardiovascular DiseasesLipoproteins and Cardiovascular Health

Deficiency of ATP-Binding Cassette Transporters A1 and G1 in Endothelial Cells Accelerates Atherosclerosis in Mice

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Westerterp, Marit, Tsuchiya, Kyoichiro, Tattersall, Ian W., Fotakis, Panagiotis, Bochem, Andrea E., Molusky, Matthew M., Ntonga, Vusisizwe, Abramowicz, Sandra +5 more·2016·Arteriosclerosis, Thrombosis, and Vascular Biology
DOI 10.1161/atvbaha.115.306670PMC PMC4919153
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Abstract

Objective—: Plasma high-density lipoproteins have several putative antiatherogenic effects, including preservation of endothelial functions. This is thought to be mediated, in part, by the ability of high-density lipoproteins to promote cholesterol efflux from endothelial cells (ECs). The ATP-binding cassette transporters A1 and G1 (ABCA1 and ABCG1) interact with high-density lipoproteins to promote cholesterol efflux from ECs. To determine the impact of endothelial cholesterol efflux pathways on atherogenesis, we prepared mice with endothelium-specific knockout of Abca1 and Abcg1 . Approach and Results—: Generation of mice with EC-ABCA1 and ABCG1 deficiency required crossbreeding Abca1 fl/fl Abcg1 fl/fl Ldlr −/− mice with the Tie2Cre strain, followed by irradiation and transplantation of Abca1 fl/fl Abcg1 fl/fl bone marrow to abrogate the effects of macrophage ABCA1 and ABCG1 deficiency induced by Tie2Cre. After 20 to 22 weeks of Western-type diet, both single EC- Abca1 and Abcg1 deficiency increased atherosclerosis in the aortic root and whole aorta. Combined EC- Abca1/g1 deficiency caused a significant further increase in lesion area at both sites. EC- Abca1/g1 deficiency dramatically enhanced macrophage lipid accumulation in the branches of the aorta that are exposed to disturbed blood flow, decreased aortic endothelial NO synthase activity, and increased monocyte infiltration into the atherosclerotic plaque. Abca1/g1 deficiency enhanced lipopolysaccharide-induced inflammatory gene expression in mouse aortic ECs, which was recapitulated by ABCG1 deficiency in human aortic ECs. Conclusions—: These studies provide direct evidence that endothelial cholesterol efflux pathways mediated by ABCA1 and ABCG1 are nonredundant and atheroprotective, reflecting preservation of endothelial NO synthase activity and suppression of endothelial inflammation, especially in regions of disturbed arterial blood flow.

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  • Endothelial cell knockout of ABCA1 alone did not result in alterations in new vessel sprouting in a murine model of atherosclerosis, while knockout of ABCG1 did.

    “However, endothelial cell knockout of ABCA1 alone did not result in alterations in new vessel sprouting in a murine model of atherosclerosis, while knockout of ABCG1 did (58).”

    From Cholesterol efflux protein, ABCA1, supports anticancer functions of myeloid immune cells (2026) · cites this paper as [58]

    The Results section ('EC-Abca1 and Abcg1 deficiency enhance new vessel sprouting in aortic rings'; page not provided) reports increased sprouting with endothelial Abcg1 knockout, but not Abca1 knockout. That finding came from an ex vivo aortic-ring assay, not a measurement of sprouting in atherosclerotic lesions; the paper reports no difference in new blood vessels in those lesions. (LLM, conf=0.85)

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Cited by

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Authors
Westerterp, M., Tsuchiya, K., Tattersall, I. W., Fotakis, P., Bochem, A. E., Molusky, M. M., Ntonga, V., Abramowicz, S., Parks, J. S., Welch, C. L., Kitajewski, J., Accili, D., & Tall, A. R.
Affiliations
Tokyo Medical and Dental University (JP)
Corresponding author
Westerterp, Marit
ORCID
Venue
Arteriosclerosis, Thrombosis, and Vascular Biology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2016-07
Volume
36
Issue
7
Pages
1328-1337
ISSN
  • 1079-5642 (ISSN-L)
  • 1524-4636
DOI
10.1161/atvbaha.115.306670
PMC
PMC4919153
OpenAlex
W2403798563
Cited by
114
References
5
Citations by year
2026: 5 · 2025: 7 · 2024: 8 · 2023: 13 · 2022: 13 · 2021: 9 · 2020: 19 · 2019: 9 · 2018: 20 · 2017: 8 · 2016: 3
FWCI
14.77
Type
journal article
Language
en
Open access
Locations
  • Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
Funders
  • National Heart, Lung, and Blood Institute (R01HL119043, R01HL119962, P01HL087123, R01HL112626, R01HL107653, T32HL007343)
  • National Center for Research Resources (S10RR027050)
Topics
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
Keywords
ABCA1, ABCG1, ABC transporters, endothelial cells, atherosclerosis, cholesterol efflux, high-density lipoprotein, endothelial nitric oxide synthase, endothelial inflammation, disturbed blood flow, macrophage lipid accumulation, monocyte infiltration, lipopolysaccharide, aortic plaque
MeSH terms
ATP Binding Cassette Transporter, Subfamily G, Member 1, Animals, Aorta, Thoracic, Aortic Diseases, Cholesterol, Disease Models, Animal, Macrophages, Male, Monocytes, Phenotype, Receptors, LDL, Regional Blood Flow, Time Factors, Whole-Body Irradiation, Retinal Neovascularization, Bone Marrow Transplantation, Mice, Knockout, Disease Progression, Inflammation Mediators, Neovascularization, Physiologic, Genetic Predisposition to Disease, Endothelial Cells, Tissue Culture Techniques, Atherosclerosis, Nitric Oxide Synthase Type III, Plaque, Atherosclerotic, Diet, High-Fat, ATP Binding Cassette Transporter 1

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