title: Endothelial expression of human ABCA1 in mice increases plasma HDL cholesterol and reduces diet-induced atherosclerosis.
abstract: The role of endothelial ABCA1 expression in reverse cholesterol transport (RCT) was examined in transgenic mice, using the endothelial-specific Tie2 promoter. Human ABCA1 (hABCA1) was significantly expressed in endothelial cells (EC) of most tissues except the liver. Increased expression of ABCA1 was not observed in resident peritoneal macrophages. ApoA-I-mediated cholesterol efflux from aortic EC was 2.6-fold higher (P < 0.0001) for cells from transgenic versus control mice. On normal chow diet, Tie2 hABCA1 transgenic mice had a 25% (P < 0.0001) increase in HDL-cholesterol (HDL-C) and more than a 2-fold increase of eNOS mRNA in the aorta (P < 0.04). After 6 months on a high-fat, high-cholesterol (HFHC) diet, transgenic mice compared with controls had a 40% increase in plasma HDL-C (P < 0.003) and close to 40% decrease in aortic lesions (P < 0.02). Aortas from HFHC-fed transgenic mice also showed gene expression changes consistent with decreased inflammation and apoptosis. Beneficial effects of the ABCA1 transgene on HDL-C levels or on atherosclerosis were absent when the transgene was transferred onto ApoE or Abca1 knockout mice. In summary, expression of hABCA1 in EC appears to play a role in decreasing diet-induced atherosclerosis in mice and is associated with increased plasma HDL-C levels and beneficial gene expression changes in EC.
authors: Cardiovascular-Pulmonary Branch, National Heart, Lung, and Blood Institute, Clinical Center, National Institutes of Health, Bethesda, MD, USA. borisv@mail.nih.gov
authors: Boris L
authors: BL
authors: Vaisman
authors: Stephen J
authors: SJ
authors: Demosky
authors: John A
authors: JA
authors: Stonik
authors: Mona
authors: M
authors: Ghias
authors: Cathy L
authors: CL
authors: Knapper
authors: Maureen L
authors: ML
authors: Sampson
authors: Cuilian
authors: C
authors: Dai
authors: Stewart J
authors: SJ
authors: Levine
authors: Alan T
authors: AT
authors: Remaley
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis*; D000818:Animals; D001011:Aorta / Q000378:metabolism; D016632:Apolipoprotein A-I / Q000378:metabolism; D050197:Atherosclerosis / Q000517:prevention & control*; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D008076:Cholesterol, HDL / Q000097:blood*; D004041:Dietary Fats / Q000008:administration & dosage; D004730:Endothelium, Vascular / Q000378:metabolism*; D005260:Female; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D002791:Cholesterol, Dietary; D008076:Cholesterol, HDL; D004041:Dietary Fats