Published online before print September 8, 2005, doi: 10.1161/01.RES.0000185320.82962.F7
© 2005 American Heart Association, Inc.
Integrative Physiology |
Increased Atherosclerosis in Mice Lacking Apolipoprotein A-I Attributable to Both Impaired Reverse Cholesterol Transport and Increased Inflammation
From the Institute for Translational Medicine and Therapeutics (R.E.M., J.S.M., D.J.R.), University of Pennsylvania School of Medicine, Philadelphia; Department of Medicine (M.N., S.H.), David Geffen School of Medicine at UCLA, Los Angeles, Calif; and Division of Gastroenterology and Nutrition (F.Z., G.H.R.), Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pa.
Correspondence to Daniel J. Rader, Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, 654 BRB II/III, 421 Curie Blvd, Philadelphia, PA 19104. E-mail rader{at}mail.med.upenn.edu
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.
Key Words: antioxidant enzymes • atherosclerosis • lipoproteins • apolipoprotein A-I
This article has been cited by other articles:
 |
|
 |
|
  L. Calpe-Berdiel, N. Rotllan, C. Fievet, R. Roig, F. Blanco-Vaca, and J. C. Escola-Gil Liver X receptor-mediated activation of reverse cholesterol transport from macrophages to feces in vivo requires ABCG5/G8 J. Lipid Res., September 1, 2008; 49(9): 1904 - 1911. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. M. deGoma, R. L. deGoma, and D. J. Rader Beyond high-density lipoprotein cholesterol levels evaluating high-density lipoprotein function as influenced by novel therapeutic approaches. J. Am. Coll. Cardiol., June 10, 2008; 51(23): 2199 - 2211. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Tanigawa, J. T. Billheimer, J.-i. Tohyama, Y. Zhang, G. Rothblat, and D. J. Rader Expression of Cholesteryl Ester Transfer Protein in Mice Promotes Macrophage Reverse Cholesterol Transport Circulation, September 11, 2007; 116(11): 1267 - 1273. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Parastatidis, L. Thomson, D. M. Fries, R. E. Moore, J. Tohyama, X. Fu, S. L. Hazen, H. F.G. Heijnen, M. K. Dennehy, D. C. Liebler, et al. Increased Protein Nitration Burden in the Atherosclerotic Lesions and Plasma of Apolipoprotein A-I Deficient Mice Circ. Res., August 17, 2007; 101(4): 368 - 376. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-Y. Lee, R. M. Badeau, A. Mulya, E. Boudyguina, A. K. Gebre, T. L. Smith, and J. S. Parks Functional LCAT deficiency in human apolipoprotein A-I transgenic, SR-BI knockout mice J. Lipid Res., May 1, 2007; 48(5): 1052 - 1061. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Favari, M. Gomaraschi, I. Zanotti, F. Bernini, M. Lee-Rueckert, P. T. Kovanen, C. R. Sirtori, G. Franceschini, and L. Calabresi A Unique Protease-sensitive High Density Lipoprotein Particle Containing the Apolipoprotein A-IMilano Dimer Effectively Promotes ATP-binding Cassette A1-mediated Cell Cholesterol Efflux J. Biol. Chem., February 23, 2007; 282(8): 5125 - 5132. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Zabalawi, M. Bharadwaj, H. Horton, M. Cline, M. Willingham, M. J. Thomas, and M. G. Sorci-Thomas Inflammation and skin cholesterol in LDLr-/-, apoA-I-/- mice: link between cholesterol homeostasis and self-tolerance? J. Lipid Res., January 1, 2007; 48(1): 52 - 65. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Wang, B. G. Sharifi, T. Pan, L. Song, A. Yukht, and P. K. Shah Bone Marrow Transplantation Shows Superior Atheroprotective Effects of Gene Therapy With Apolipoprotein A-I Milano Compared With Wild-Type Apolipoprotein A-I in Hyperlipidemic Mice J. Am. Coll. Cardiol., October 3, 2006; 48(7): 1459 - 1468. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Kontush and M. J. Chapman Functionally Defective High-Density Lipoprotein: A New Therapeutic Target at the Crossroads of Dyslipidemia, Inflammation, and Atherosclerosis Pharmacol. Rev., September 1, 2006; 58(3): 342 - 374. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Rashid, B. W. Patterson, and G. F. Lewis Thematic review series: Patient-Oriented Research. What have we learned about HDL metabolism from kinetics studies in humans? J. Lipid Res., August 1, 2006; 47(8): 1631 - 1642. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Cuchel and D. J. Rader Macrophage Reverse Cholesterol Transport: Key to the Regression of Atherosclerosis? Circulation, May 30, 2006; 113(21): 2548 - 2555. [Full Text] [PDF]
|
|
|
|
|
|
M. Navab, G.M. Anantharamaiah, and A. M. Fogelman An Apolipoprotein A-I Mimetic Works Best in the Presence of Apolipoprotein A-I Circ. Res., November 25, 2005; 97(11): 1085 - 1086. [Full Text] [PDF]
|
|