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Combined deficiency of ABCA1 and ABCG1 promotes foam cell accumulation and accelerates atherosclerosis in mice.

ABSTRACT: HDLs protect against the development of atherosclerosis, but the underlying mechanisms are poorly understood. HDL and its apolipoproteins can promote cholesterol efflux from macrophage foam cells via the ATP-binding cassette transporters ABCA1 and ABCG1. Experiments addressing the individual roles of ABCA1 and ABCG1 in the development of atherosclerosis have produced mixed results, perhaps because of compensatory upregulation in the individual KO models. To clarify the role of transporter-mediated sterol efflux in this disease process, we transplanted BM from Abca1(-/-)Abcg1(-/-) mice into LDL receptor-deficient mice and administered a high-cholesterol diet. Compared with control and single-KO BM recipients, Abca1(-/-)Abcg1(-/-) BM recipients showed accelerated atherosclerosis and extensive infiltration of the myocardium and spleen with macrophage foam cells. In experiments with isolated macrophages, combined ABCA1 and ABCG1 deficiency resulted in impaired cholesterol efflux to HDL or apoA-1, profoundly decreased apoE secretion, and increased secretion of inflammatory cytokines and chemokines. In addition, these cells showed increased apoptosis when challenged with free cholesterol or oxidized LDL loading. These results suggest that the combined effects of ABCA1 and ABCG1 in mediating macrophage sterol efflux are central to the antiatherogenic properties of HDL.

SUBMITTER: Yvan-Charvet L

PROVIDER: S-EPMC2066200 | biostudies-literature | 2007 Dec

REPOSITORIES: biostudies-literature

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Combined deficiency of ABCA1 and ABCG1 promotes foam cell accumulation and accelerates atherosclerosis in mice.

Yvan-Charvet Laurent L Ranalletta Mollie M Wang Nan N Han Seongah S Terasaka Naoki N Li Rong R Welch Carrie C Tall Alan R AR

The Journal of clinical investigation 20071201 12

HDLs protect against the development of atherosclerosis, but the underlying mechanisms are poorly understood. HDL and its apolipoproteins can promote cholesterol efflux from macrophage foam cells via the ATP-binding cassette transporters ABCA1 and ABCG1. Experiments addressing the individual roles of ABCA1 and ABCG1 in the development of atherosclerosis have produced mixed results, perhaps because of compensatory upregulation in the individual KO models. To clarify the role of transporter-mediat ...[more]

PMID: 17992262

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Project description:BackgroundSmooth muscle cells (SMCs) regulate blood flow distribution via vasoconstriction mediated by α-ARs (α-adrenergic receptors). Plasma membrane cholesterol accumulation affects α1-AR signaling and promotes loss of SMC contractile markers in vitro. ABCA1 and ABCG1 (ATP-binding cassette transporter A1 and G1) mediate cholesterol efflux to HDL (high-density lipoprotein). ABCA1/ABCG1 show high expression in medial and low expression in intimal SMCs of atherosclerotic plaques. The role of ABCA1 and ABCG1 in SMC-mediated vasoconstriction and atherogenesis remains poorly understood.MethodsWe generated mice with SMC-specific Abca1/Abcg1 deficiency on the low-density lipoprotein receptor-deficient (Ldlr-/-) background by crossbreeding Abca1fl/flAbcg1fl/flLdlr-/- mice with Myh11CreERT2 transgenic mice. To induce SMC cholesterol accumulation and atherogenesis, we fed Myh11CreERT2Abca1fl/flAbcg1fl/flLdlr-/-, Myh11CreERT2Abca1fl/flLdlr-/-, Myh11CreERT2Abcg1fl/flLdlr-/-, and Myh11CreERT2Ldlr-/- mice Western-type diet for 16 weeks.ResultsCombined SMC-Abca1/Abcg1 deficiency increased vasoconstriction in aortic rings induced by the α1-AR agonist phenylephrine. Unexpectedly, SMC-Abca1/Abcg1 deficiency induced urinary bladder distension by >20-fold. This was reversed by the α1-AR antagonist tamsulosin, indicating its dependence on bladder neck SMC constriction. Moreover, SMC-Abca1/Abcg1 deficiency decreased contractile markers and increased macrophage and fibroblast markers in bladder SMCs, indicating SMC transdifferentiation. This was accompanied by free cholesterol accumulation and increased endoplasmic reticulum stress. SMC-Abca1/Abcg1 deficiency did not induce thoracic aorta SMC transdifferentiation, presumably due to increased cholesteryl ester accumulation and no endoplasmic reticulum stress in thoracic aorta SMCs. Surprisingly, SMC-Abca1/Abcg1 deficiency did not affect atherosclerotic lesion size or composition in the aortic root or brachiocephalic artery.ConclusionsWe uncover a new role of SMC cholesterol efflux pathways in suppressing α1-AR-mediated vasoconstriction and bladder SMC transdifferentiation, decreasing urinary bladder distension. Our data may provide a mechanistic link for the association between urinary bladder distension and diabetes in humans, particularly because diabetes is associated with decreased cholesterol efflux. SMC-Abca1/Abcg1 deficiency did not affect atherosclerotic lesion size or plaque composition, presumably due to low expression of Abca1/Abcg1 in intimal SMCs.

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Combined deficiency of ABCA1 and ABCG1 promotes foam cell accumulation and accelerates atherosclerosis in mice.

Publications

Combined deficiency of ABCA1 and ABCG1 promotes foam cell accumulation and accelerates atherosclerosis in mice.

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