To test the hypothesis that apolipoprotein A-I (apoA-I) functions specifically to inhibit atherosclerosis independent of the level of high-density lipoprotein cholesterol (HDL-C) by promoting both reverse cholesterol transport and HDL antiinflammatory function in vivo, we established a murine atherosclerosis model of apoA-I deficiency in which the level of HDL-C is well maintained. ApoA-I-/- mice were crossed with atherosclerosis susceptible low-density lipoprotein receptor-/-/apobec-/- (LA) mice to generate LA mice with apoA-I+/+, apoA-I+/-, and apoA-I-/- genotypes. There were no major differences in the amounts of non-HDL-C and HDL-C in the plasma between different apoA-I genotypes. A significant inverse relationship was observed, however, between apoA-I gene dose and atherosclerosis in both female and male mice. Compared with LA-apoA-I+/+ mice, serum from LA-apoA-I-/- mice had a significantly reduced capacity to function as an acceptor of ABCA1- and SR-BI-mediated cellular cholesterol efflux, and also had markedly reduced lecithin cholesterol acyltransferase activity. In addition, LA-apoA-I-/- mice had significantly reduced macrophage-derived cholesterol esterification and reverse cholesterol transport in vivo. There was significantly reduced plasma paraoxonase (PON-1) activity, impaired HDL vascular antiinflammatory function, and increased basal levels of monocyte chemotactic protein-1 in the plasma of LA-apoA-I-/- mice compared with LA-apoA-I+/+ mice. In LA-apoA-I-/- mice, there was also greater induction of some, but not all, inflammatory cytokines and chemokines in response to intraperitoneal injection of lipopolysaccharide than in LA-apoA-I+/+ mice. We conclude that apoA-I inhibits atherosclerosis by promoting both macrophage reverse cholesterol transport and HDL antiinflammatory function, and that these anti-atherogenic functions of apoA-I are largely independent of the plasma level of HDL-C in this mouse model.
Increased Atherosclerosis in Mice Lacking Apolipoprotein A-I Attributable to Both Impaired Reverse Cholesterol Transport and Increased Inflammation / R. E., Moore; M., Navab; J. S., Millar; Zimetti, Francesca; G. H., Rothblat; D. J., Rader. - In: CIRCULATION RESEARCH. - ISSN 0009-7330. - 97:(2005), pp. 763-771. [10.1161/01.RES.0000185320.82962.F7]
Increased Atherosclerosis in Mice Lacking Apolipoprotein A-I Attributable to Both Impaired Reverse Cholesterol Transport and Increased Inflammation
ZIMETTI, Francesca;
2005-01-01
Abstract
To test the hypothesis that apolipoprotein A-I (apoA-I) functions specifically to inhibit atherosclerosis independent of the level of high-density lipoprotein cholesterol (HDL-C) by promoting both reverse cholesterol transport and HDL antiinflammatory function in vivo, we established a murine atherosclerosis model of apoA-I deficiency in which the level of HDL-C is well maintained. ApoA-I-/- mice were crossed with atherosclerosis susceptible low-density lipoprotein receptor-/-/apobec-/- (LA) mice to generate LA mice with apoA-I+/+, apoA-I+/-, and apoA-I-/- genotypes. There were no major differences in the amounts of non-HDL-C and HDL-C in the plasma between different apoA-I genotypes. A significant inverse relationship was observed, however, between apoA-I gene dose and atherosclerosis in both female and male mice. Compared with LA-apoA-I+/+ mice, serum from LA-apoA-I-/- mice had a significantly reduced capacity to function as an acceptor of ABCA1- and SR-BI-mediated cellular cholesterol efflux, and also had markedly reduced lecithin cholesterol acyltransferase activity. In addition, LA-apoA-I-/- mice had significantly reduced macrophage-derived cholesterol esterification and reverse cholesterol transport in vivo. There was significantly reduced plasma paraoxonase (PON-1) activity, impaired HDL vascular antiinflammatory function, and increased basal levels of monocyte chemotactic protein-1 in the plasma of LA-apoA-I-/- mice compared with LA-apoA-I+/+ mice. In LA-apoA-I-/- mice, there was also greater induction of some, but not all, inflammatory cytokines and chemokines in response to intraperitoneal injection of lipopolysaccharide than in LA-apoA-I+/+ mice. We conclude that apoA-I inhibits atherosclerosis by promoting both macrophage reverse cholesterol transport and HDL antiinflammatory function, and that these anti-atherogenic functions of apoA-I are largely independent of the plasma level of HDL-C in this mouse model.File | Dimensione | Formato | |
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