This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shah, P. K. Articles by Cercek, B. Search for Related Content PubMed PubMed Citation Articles by Shah, P. K. Articles by Cercek, B. Related Collections Other Stroke Treatment - Surgical Cardiovascular Pharmacology

(Circulation. 2001;104:2498.)
© 2001 American Heart Association, Inc.

From Bench to Bedside

Exploiting the Vascular Protective Effects of High-Density Lipoprotein and its Apolipoproteins

An Idea Whose Time for Testing Is Coming, Part II

Prediman K. Shah, MD; Sanjay Kaul, MD; Jan Nilsson, MD, PhD; Bojan Cercek, MD, PhD

From the Atherosclerosis Research Center, Division of Cardiology and Burns and Allen research Institute, Department of Medicine, Cedars Sinai Medical Center and UCLA School of Medicine (P.K.S., S.K., B.C.), Los Angeles, Calif, and the University of Malmo, Lund, Sweden (J.N).

Correspondence to P.K. Shah, MD, Director, Division of Cardiology and Atherosclerosis Research Center, Room 5347, Cedars Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048. E-mail shahp{at}cshs.org

Key Words: lipoproteins • atherosclerosis • apolipoproteins

	Introduction

Top Introduction Structural and Functional... Conclusions References

 
Despite the benefits of currently available preventative and therapeutic interventions, atherosclerotic vascular disease continues to be a major cause of morbidity and mortality in much of the Western world. This emphasizes the need for additional preventive and therapeutic interventions exploiting new targets to compliment and augment the results of LDL lowering and other current strategies. One such potential target is HDL and its apolipoproteins. A large body of experimental evidence suggests that augmenting the levels and/or function of HDL and its apolipoproteins can have major vascular protective effects ranging from prevention to stabilization and regression, independent of total or non-HDL cholesterol levels. Therefore, we think that the time is ripe for the development and clinical testing of this new frontier in antiatherogenic strategy. In the present article, we will review the structure/function of HDL and explore means of enhancing the levels and/or function of HDL and its apolipoproteins for vascular protection.

	Structural and Functional Heterogeneity of HDL Particles

Top Introduction Structural and Functional... Conclusions References

 
HDL cholesterol particles consist of an outer amphipathic layer of free cholesterol, phospholipid, and several apolipoproteins (apolipoprotein A-I [the most abundant] and apolipoproteins AII, C, E, AIV, J [clusterin], and D) on the surface, with a triglyceride and cholesterol ester–rich hydrophobic core. Apolipoprotein A-I constitutes 70% and apolipoprotein A-II makes up 20% of the protein content of HDL. Apolipoprotein A-I is synthesized in the liver and intestines in man and mice (and mostly in the intestines in rabbits), whereas apolipoprotein A-II is synthesized mostly in the liver. The gene for apolipoprotein A-I is located on chromosome 11 adjacent to the gene cluster for apolipoproteins CIII and A-IV. Apolipoprotein A-I is synthesized as a 260-amino acid prepropeptide, which is cleaved to a 249-amino acid propeptide, which in turn is cleaved to the 243-amino acid, mature apolipoprotein A-I after secretion out of the cell.

Apolipoprotein A-I is the principal protein of HDL; it contains a globular N-terminal domain (residues 1 to 43) and a lipid-binding C-terminal domain (residues 44 to 243). Human apolipoprotein A-I possesses multiple tandem repeating 22-mer amphipathic -helixes. Computer analysis and studies of model synthetic peptides and recombinant protein-lipid complexes of phospholipids have suggested that apolipoprotein A-I interacts with HDL surface lipids through cooperation among its individual amphipathic helical domains. In mature human apolipoprotein A-I, the amino acid residues 1 to 43 are encoded by exon 3, whereas residues 44 to 243 are encoded by exon 4 of the apolipoprotein A-I gene. The region encoded by exon 4 of the apolipoprotein A-I gene contains 10 tandem amphipathic -helixes; their location and the class to which they belong are as follows: helix 1 (44 to 65, class A1), helix 2 (66 to 87, class A1), helix 3 (88 to 98, class Y), helix 4 (99 to 120, class Y), helix 5 (121 to 142, class A1), helix 6 (143 to 164, class A1), helix 7 (165 to 186, class A1), helix 8 (187 to 208, class A1), helix 9 (209 to 219, class Y), and helix 10 (220 to 241, class Y).¹

The antiatherogenic effects of HDL are thought to be largely due to apolipoprotein A-I; however, apolipoprotein AIV and apolipoprotein E may also have antiatherogenic effects.^2–9 HDL particles also carry other molecules, such as paraoxonase, platelet activating factor-acetylhydrolase, lecithin cholesterol acyltransferase (LCAT), and cholesterol ester transfer protein (CETP). HDL particles demonstrate -mobility and have been characterized into several subtypes on the basis of density ultracentrifugation; these subtypes include HDL-2 (density, 1.063 to 1.125 g/mL; particle size, 11 to 12 nm) and HDL-3 (density, 1.125 to 1.21 g/mL; particle size, 9 to 10 nm). The differences in particle size results mainly from the number of apolipoprotein molecules and the volume of the cholesterol ester in the core of the particle. The immunoaffinity technique has shown that some of the HDL particles carry only apolipoprotein A-I (LPA-I), whereas others carry both apolipoprotein A-I and A-II (LPA-I A-II). On agarose gel electrophoresis, HDL separates as an -particle, although a small fraction of HDL, pre-ß-HDL, has been identified by Fielding and Fielding.¹⁰ This particle may play a key role in the early steps of reverse cholesterol transport.

It has been shown that the antioxidant enzyme paraoxonase is carried only by apolipoprotein A-I and apolipoprotein J–containing HDL subspecies.^7,11–31 The cholesterol efflux–promoting capacity is generally attributed to subspecies containing apolipoprotein A-I.^32–38 Several naturally occurring mutants of apolipoprotein A-I have been described; these mutants are generally associated with reduced HDL cholesterol and apolipoprotein A-I levels, most often related to accelerated catabolism rather than reduced synthesis of apolipoprotein A-I. Although some of these hypoalphlipoproteienemic states are associated with an increased risk of atherosclerotic vascular disease, others do not seem to predispose to accelerated or premature vascular disease.^39–41 In fact, there is evidence to suggest that one such mutant, apolipoprotein A-I_Milano, which is inherited as an autosomal-dominant trait among a small number of inhabitants of Limone Sul Garda in Northern Italy, may actually be associated with longevity and protection from vascular disease.^40,41

Apolipoprotein A-I_Milano is the result of a point mutation, with an arginine to cysteine substitution at position173.⁴¹ The carriers of this mutation are all heterozygotes who exhibit hypertriglyceridemia with markedly reduced HDL and apolipoprotein A-I levels, and mutant apolipoprotein A-I constitutes 80% of the total apolipoprotein A-I content. The presence of a cysteine residue at position 173 results in the formation of homodimers with wild-type apolipoprotein A-I and heterodimers with apolipoprotein A-II. The absence of vascular disease in the carriers of apolipoprotein A-I_Milano has been attributed to the increased efficiency of the mutant in promoting reverse cholesterol transport. This conjecture is supported by in vitro data from our laboratory and by data reported by Franceschini et al.⁴² However, opposite results have been reported by Bielicki et al⁴³ using a different in vitro model system.

Strategies for Increasing Circulating and/or Arterial Wall HDL/Apolipoprotein A-I Levels
Circulating HDL and apolipoprotein A-I levels can be increased directly by increasing the synthesis of apolipoprotein A-I and/or by inhibiting the clearance of apolipoprotein A-I. Circulating HDL levels tend to increase with regular dynamic exercise, modest alcohol consumption, weight loss, a high fat diet, and smoking cessation, whereas they tend to decrease with obesity, menopause, high carbohydrate diets, and smoking.^44–47 Pharmacological agents that increase HDL include hydroxymethylglutaryl coenzyme A reductase inhibitors (statins), niacin, fibric acid derivatives, Dilantin (phenytoin), chromium picolonate, and female hormone replacement therapy.⁴⁶ However, the magnitude of HDL elevation is variable, ranging from small increases with statins to larger increases with niacin and fibrates. Among statins, there seem to be differences in the magnitude of the HDL increases observed. Thus, high-dose simvastatin produces a relatively greater increase in HDL than does high-dose atorvastatin, despite significant and comparable reductions in LDL cholesterol.^47,48 These findings suggest that all statins may not be similar in terms of their pleiotropic effects other than LDL-lowering. Statin-induced inhibition of the Rho-signaling pathway activates peroxisomal proliferator activated receptor- (PPAR-), thereby inducing the transcription of the apolipoprotein A-I gene, which thus provides a molecular basis for the increase in HDL by statins.⁴⁹

Given the structural heterogeneity of HDL with respect to its apolipoprotein composition and consequent functional heterogeneity, it is unclear which one of these interventions and to what extent they increase the functionally protective species of HDL particles (apolipoprotein A-I–only containing particles [LPA-I] and apolipoprotein E–containing particles). Other approaches to increasing HDL include use of new drugs/antibodies to inhibit CETP.⁵⁰ The relationship between CETP and atherosclerosis is complex, and both proatherogenic and antiatherogenic effects have been suggested.⁵¹ CETP may be atherogenic because of its ability to transfer cholesterol ester from HDL to LDL/VLDL, thus lowering plasma levels of HDL while increasing the levels of LDL/VLDL. Conversely, CETP may also be antiatherogenic by facilitating the production of lipid-poor pre-ß-HDL particles, which are efficient stimulators of reverse cholesterol transport.⁵¹ Both experimental and human epidemiological studies have provided conflicting data.⁵¹ A vaccine made from a peptide containing a region of CETP known to be necessary for neutral lipid transfer has been shown to stimulate antibodies against CETP, leading to an inhibition of CETP, an increase in HDL cholesterol, and a reduction of fatty streaks in cholesterol-fed rabbits, thus providing a novel mechanism for increasing HDL cholesterol levels.⁵² In view of the complex relationship between CETP and atherosclerosis, it is uncertain whether this approach will provide a viable strategy for humans.

A more direct approach for exploiting the vascular protective effects of HDL and apolipoprotein A-I would be the actual administration of plasma-derived or recombinant HDL/apolipoprotein A-I as a drug. The feasibility and efficacy of this approach has been demonstrated in our laboratory in the animal model. Studies in our laboratory have shown that repeated administration of the recombinant apolipoprotein A-I_Milano–phospholipid complex substantially reduces ileofemoral atherosclerosis in cholesterol-fed rabbits subjected to balloon injury⁵³ and prevents the progression of atherosclerosis.⁵⁴ At high doses, it promotes the regression of aortic atheromatosis in cholesterol-fed apolipoprotein E–null mice, despite severe hypercholesterolemia.⁵⁴ Furthermore, the recombinant apolipoprotein A-I_Milano–phospholipid complex therapy was also shown to decrease lipid and macrophage content, thus promoting a more stable plaque-phenotype in apolipoprotein E–null mice, both during repeated administration and after single high-dose administration.^54,55 Furthermore, in vitro studies have demonstrated that both wild-type apolipoprotein A-I and apolipoprotein A-I_Milano reduce the proapoptotic effect of oxysterols (produced during LDL oxidation) on vascular smooth muscle cells, which may further help preserve the integrity of the smooth muscle cell–rich cap of the atherosclerotic plaque.⁵⁶ Wild-type plasma-derived HDL has also been shown to reduce neointimal thickening in a perivascular cuff–induced carotid arterial injury model in apolipoprotein E–null mice.⁵⁷ Because inflammation is thought to play an important role in arterial response to injury, the anti-inflammatory effects of HDL may be the underlying mechanism for the reduction in neointimal thickening.^57,58

Human Studies With Reconstituted Wild-Type HDL and Pro-Apolipoprotein A-I
Preliminary studies by Nanjee et al^59,60 have shown that the intravenous injection of discs containing apolipoprotein A-I and phosphatidylcholine increase the intravascular production of small pre-ß-HDL particles in vivo and are associated with an increase in the efflux and esterification of tissue-derived unesterified cholesterol in normal healthy male volunteers. Similarly, Eriksson et al⁶¹ demonstrated increased fecal excretion of cholesterol after the intravenous injection of liposomes containing pro-apolipoprotein A-I (a precursor of apolipoprotein A-I).

Apolipoprotein A-I or HDL Mimetic Synthetic Peptides
Dimeric lipid-free synthetic peptides containing 18-mer amphipathic helices of the class found in HDL apolipoproteins (class A) have been shown to promote reverse cholesterol transport in cultured cholesterol-laden fibroblasts and macrophages and to interact with cell-surface HDL binding sites, thus simulating many of the biological effects of HDL.^62,63 Thus, synthetic peptides comprising dimers of a structural motif common to exchangeable apolipoproteins can mimic apolipoprotein A-I in both binding to putative cell-surface receptors and in clearing cholesterol from cells. Several such peptide mimetics are being developed for further preclinical and clinical testing by different pharmaceutical companies.

Unilamellar Phospholipid Vesicles
Several experimental studies have also suggested that large unilamellar phospholipid vesicles or liposomes, when administered intravenously in large amounts, may stimulate reverse cholesterol transport and, thereby, have potential antiatherogenic effects analogous to those of HDL.^64–66 Whether these beneficial effects are similar to or different from those of the apolipoprotein A-I–phospholipid complex are presently unknown, because no comparative data are available. However, further evaluation of this approach is warranted.

Apolipoprotein A-I Gene Transfer
Several preclinical studies have shown the feasibility and efficacy of apolipoprotein A-I gene transfer in inhibiting the progression and promoting the regression of atherosclerosis in murine models.^67–70

Other HDL-Related Gene Targets
Other genes that may influence HDL structure or function or be involved in reverse cholesterol transport may also have antiatherogenic effects. These potential HDL-associated genes include lecithin cholesterol acyltransferase (LCAT; especially in species with CETP), apolipoprotein E, apolipoprotein A-IV, paraoxonase, platelet activating factor acetylhydrolase (PAF-AH), scavenger receptor (SR)-B1, and ABC-AI ((ATP binding cassette transporter). Although gene therapy continues to evolve as a therapeutic strategy, several obstacles need to be overcome before the promise of gene therapy as a clinically effective modality becomes a reality. Current gene therapy approaches are limited by the inefficiency of the vector, the transient and inefficient nature of gene expression, and the potential for an immunological reaction to the vector and to the transgene. To make gene therapy a viable option, several issues need to be addressed. These include the following: selecting a highly efficient, nonpathogenic vector; selecting the most appropriate method and site of gene delivery for optimum effectiveness; ensuring high levels of transgene expression; ensuring prolonged and stable expression of therapeutic genes, without an adverse immune response; and ensuring that random integration and germline transmission of viral vectors with potentially adverse effects does not occur. At the present time, none of these issues have been resolved, although steady progress is being made. It is likely that over the next several years, improvements in vectors and delivery techniques, which will allow for prolonged or possibly stable perpetual expression of therapeutic genes, will make gene therapy a viable option for atherothrombotic vascular disease.

We recently demonstrated successful transfer of the apolipoprotein A-I_Milano gene into vascular smooth muscle cells, endothelial cells, and bone marrow cells using recombinant adeno-associated virus (AAV) driven by Rous sarcoma virus and cytomegalovirus promoters. Vessel wall–specific targeting of the apolipoprotein A-I gene may also be achieved through local delivery of the gene at the time of endovascular intervention, intrapericardial delivery for coronary artery targeting, or through bone marrow or stem cells/macrophage–mediated gene transfer.

Other Approaches
Recent unraveling of critical steps involved in reverse cholesterol transport, particularly the involvement of ABC-AI and SRB-1, have created additional novel targets for therapeutic exploitation against atherosclerosis.^71,72 Thus, pharmacologically increasing the expression or functional activity of ABC-AI to augment cholesterol efflux to apolipoprotein A-I/HDL or increasing the hepatic uptake of HDL cholesterol through the enhancement of the expression or activity of SRB-1 are strategies worth exploring. The ABC-AI gene contains elements in its promoter that are responsive to several nuclear hormone receptors, such as PPAR, PPAR, liver X receptor (LXR), and retinoid X receptor (RXR).^73–76 Recent studies have shown that a selective, orally effective synthetic PPAR agonist increases HDL cholesterol, reduces triglycerides and small dense LDL, enhances cholesterol efflux, and reduces insulin levels in a primate model of insulin resistance–type dysmetabolic syndrome.⁷⁷ Similarly, a high-affinity agonist of RXR (rexinoids) was shown to inhibit atherosclerosis markedly in apolipoprotein E–null mice; this was most likely due to the stimulation of ABC-AI mRNA levels and cholesterol efflux from macrophages in an LXR-dependent fashion.⁷⁸ Ligands of LXR also seem to (1) stimulate the expression of cholesterol 7 -hydroxylase, leading to increased biliary excretion of bile acids, (2) increase cholesterol efflux from peripheral tissues by activating ABC-AI and possibly other ABC transporters, such as ABC-G1, and (3) inhibit cholesterol absorption from the gut, possibly by activating other ATP binding transporters (ie, ABC-G5 and ABC-G8).^79,80 These observations suggest that RXR and some of its heterodimer partners may also play an important role in reverse cholesterol transport, providing attractive targets for therapeutic exploitation. Thus, the activation of specific subtypes of nuclear hormone receptors may provide a novel approach toward enhancing HDL and ABC-AI–mediated reverse cholesterol transport, with significant implications for atherosclerosis prevention and regression.

Potential Clinical Benefits of HDL/Apolipoprotein A-I Therapy
The multiple biological actions of HDL/apolipoprotein A-I coupled with promising experimental studies suggest that an HDL/apolipoprotein A-I–based therapeutic strategy could be useful against a wide variety of vaso-occlusive disorders, such as coronary artery disease (ie native coronary artery disease, vein-graft atherosclerosis, and transplant vasculopathy) and the restenosis that occurs after percutaneous transluminal coronary angioplasty (PTCA)/stenting. Therefore, we believe that the time for the evaluation of the vascular protective effects of HDL/apolipoprotein A-I is here. Therapeutic interventions targeted at enhancing HDL/apolipoprotein A-I levels or function and/or the direct administration of HDL/apolipoprotein A-I may have a major potential role against vaso-occlusive disease.

On the basis of the body of experimental and clinical data reviewed, this novel therapeutic strategy offers the possibility of promoting stabilization of atherosclerotic lesions by stimulating plaque-lipid and macrophage depletion and by improving endothelial dysfunction. Furthermore, preliminary experimental studies also raise the tantalizing possibility that adverse vascular remodeling and intimal hyperplasia responsible for post-PTCA and post-stent restenosis may also be inhibited. The antioxidant and anti-inflammatory effects of HDL/apolipoprotein A-I may contribute to the prevention of the progression of atherosclerotic lesions and possibly promote the regression of atherosclerotic disease involving the coronary, carotid, or peripheral circulation.

	Conclusions

Top Introduction Structural and Functional... Conclusions References

 
Statins and other LDL-lowering strategies have clearly contributed significantly to improved clinical outcomes in atherosclerotic vascular disease; however, heart attacks and other adverse vascular events have not disappeared with the passage of the 20th century. The time for the development and testing of novel antiatherogenic strategies, including but not limited to those exploiting the vascular protective effects of HDL/apolipoprotein A-1 and, possibly, other HDL-related atheroprotective molecules is coming.

	Footnotes

 
Dr Shah is a member of the Scientific Advisory Board of and a consultant for Esperion Therapeutics.

	References

Top Introduction Structural and Functional... Conclusions References

 

1. Segrest JP, Li L, Anantharamaiah GM, et al. Structure and function of apolipoprotein A-I and high-density lipoprotein. Curr Opin Lipidol. 2000; 11: 105–115.[Medline] [Order article via Infotrieve]
   
2. Plump AS, Scott CJ, Breslow JL. Human apolipoprotein A-I gene expression increases high density lipoprotein and suppresses atherosclerosis in the apolipoprotein E- deficient mouse. Proc Natl Acad Sci U S A. 1994; 91: 9607–9611.[Abstract/Free Full Text]
   
3. Paszty C, Maeda N, Verstuyft J, et al. Apolipoprotein AI transgene corrects apolipoprotein E deficiency-induced atherosclerosis in mice. J Clin Invest. 1994; 94: 899–903.
   
4. Liu AC, Lawn RM, Verstuyft JG, et al. Human apolipoprotein A-I prevents atherosclerosis associated with apolipoprotein[a] in transgenic mice. J Lipid Res. 1994; 35: 2263–2267.[Abstract]
   
5. Voyiaziakis E, Goldberg IJ, Plump AS, et al. ApoA-I deficiency causes both hypertriglyceridemia and increased atherosclerosis in human apoB transgenic mice. J Lipid Res. 1998; 39: 313–321.[Abstract/Free Full Text]
   
6. Schultz JR, Verstuyft JG, Gong EL, et al. Protein composition determines the anti-atherogenic properties of HDL in transgenic mice. Nature. 1993; 365: 762–764.[Medline] [Order article via Infotrieve]
   
7. Castellani LW, Navab M, Lenten BJV, et al. Overexpression of apolipoprotein AII in transgenic mice converts high density lipoproteins to proinflammatory particles. J Clin Invest. 1997; 100: 464–474.[Medline] [Order article via Infotrieve]
   
8. Warden CH, Hedrick CC, Qiao JH, et al. Atherosclerosis in transgenic mice overexpressing apolipoprotein A-II [published erratum appears in Science. 1993;262:164]. Science. 1993; 261: 469–472.[Abstract/Free Full Text]
   
9. Cohen RD, Castellani LW, Qiao JH, et al. Reduced aortic lesions and elevated high density lipoprotein levels in transgenic mice overexpressing mouse apolipoprotein A-IV. J Clin Invest. 1997; 99: 1906–1916.[Medline] [Order article via Infotrieve]
   
10. Fielding CJ, Fielding PE. Evidence for a lipoprotein carrier in human plasma catalyzing sterol efflux from cultured fibroblasts and its relationship to lecithin:cholesterol acyltransferase. Proc Natl Acad Sci U S A. 1981; 78: 3911–3914.[Abstract/Free Full Text]
    
11. Navab M, Berliner JA, Watson AD, et al. The yin and yang of oxidation in the development of the fatty streak: a review based on the 1994 George Lyman Duff Memorial Lecture. Arterioscler Thromb Vasc Biol. 1996; 16: 831–842.[Abstract/Free Full Text]
    
12. Mackness MI, Arrol S, Abbott CA, et al. Is paraoxonase related to atherosclerosis? Chem Biol Interact. 1993; 87: 161–171.[Medline] [Order article via Infotrieve]
    
13. Mackness MI, Arrol S, Abbott C, et al. Protection of low-density lipoprotein against oxidative modification by high-density lipoprotein associated paraoxonase. Atherosclerosis. 1993; 104: 129–135.[Medline] [Order article via Infotrieve]
    
14. Abbott CA, Mackness MI, Kumar S, et al. Serum paraoxonase activity, concentration, and phenotype distribution in diabetes mellitus and its relationship to serum lipids and lipoproteins. Arterioscler Thromb Vasc Biol. 1995; 15: 1812–1818.[Abstract/Free Full Text]
    
15. Sorenson RC, Primo-Parmo SL, Camper SA, et al. The genetic mapping and gene structure of mouse paraoxonase/arylesterase. Genomics. 1995; 30: 431–438.[Medline] [Order article via Infotrieve]
    
16. Mackness MI, Mackness B, Durrington PN, et al. Paraoxonase: biochemistry, genetics and relationship to plasma lipoproteins. Curr Opin Lipidol. 1996; 7: 69–76.[Medline] [Order article via Infotrieve]
    
17. Shih DM, Gu L, Hama S, et al. Genetic-dietary regulation of serum paraoxonase expression and its role in atherogenesis in a mouse model. J Clin Invest. 1996; 97: 1630–1639.[Medline] [Order article via Infotrieve]
    
18. Mackness B, Hunt R, Durrington PN, et al. Increased immunolocalization of paraoxonase, clusterin, and apolipoprotein A-I in the human artery wall with the progression of atherosclerosis. Arterioscler Thromb Vasc Biol. 1997; 17: 1233–1238.[Abstract/Free Full Text]
    
19. Graham A, Hassall DG, Rafique S, et al. Evidence for a paraoxonase-independent inhibition of low-density lipoprotein oxidation by high-density lipoprotein. Atherosclerosis. 1997; 135: 193–204.[Medline] [Order article via Infotrieve]
    
20. Luoma PV. Gene activation, apolipoprotein A-I/high density lipoprotein, atherosclerosis prevention and longevity. Pharmacol Toxicol. 1997; 81: 57–64.[Medline] [Order article via Infotrieve]
    
21. Mackness B, Mackness MI, Arrol S, et al. Effect of the human serum paraoxonase 55 and 192 genetic polymorphisms on the protection by high density lipoprotein against low density lipoprotein oxidative modification. FEBS Lett. 1998; 423: 57–60.[Medline] [Order article via Infotrieve]
    
22. Aviram M, Fuhrman B. LDL oxidation by arterial wall macrophages depends on the oxidative status in the lipoprotein and in the cells: role of prooxidants vs. antioxidants. Mol Cell Biochem. 1998; 188: 149–159.[Medline] [Order article via Infotrieve]
    
23. James RW, Blatter Garin MC, Calabresi L, et al. Modulated serum activities and concentrations of paraoxonase in high density lipoprotein deficiency states. Atherosclerosis. 1998; 139: 77–82.[Medline] [Order article via Infotrieve]
    
24. Heinecke JW, Lusis AJ. Paraoxonase-gene polymorphisms associated with coronary heart disease: support for the oxidative damage hypothesis? Am J Hum Genet. 1998; 62: 20–24.[Medline] [Order article via Infotrieve]
    
25. Mackness B, Durrington PN, Mackness MI. Human serum paraoxonase. Gen Pharmacol. 1998; 31: 329–336.[Medline] [Order article via Infotrieve]
    
26. Mackness MI, Mackness B, Durrington PN, et al. Paraoxonase and coronary heart disease. Curr Opin Lipidol. 1998; 9: 319–324.[Medline] [Order article via Infotrieve]
    
27. Aviram M, Rosenblat M, Bisgaier CL, et al. Paraoxonase inhibits high-density lipoprotein oxidation and preserves its functions: a possible peroxidative role for paraoxonase. J Clin Invest. 1998; 101: 1581–1590.[Medline] [Order article via Infotrieve]
    
28. Kwiterovich PO Jr. The antiatherogenic role of high-density lipoprotein cholesterol. Am J Cardiol. 1998; 82: 13Q–21Q.[Medline] [Order article via Infotrieve]
    
29. Shih DM, Gu L, Xia YR, et al. Mice lacking serum paraoxonase are susceptible to organophosphate toxicity and atherosclerosis. Nature. 1998; 394: 284–287.[Medline] [Order article via Infotrieve]
    
30. Aviram M. Does paraoxonase play a role in susceptibility to cardiovascular disease? Mol Med Today. 1999; 5: 381–386.[Medline] [Order article via Infotrieve]
    
31. Stein O, Stein Y. Atheroprotective mechanisms of HDL. Atherosclerosis. 1999; 144: 285–301.[Medline] [Order article via Infotrieve]
    
32. Franceschini G, Maderna P, Sirtori CR. Reverse cholesterol transport: physiology and pharmacology. Atherosclerosis. 1991; 88: 99–107.[Medline] [Order article via Infotrieve]
    
33. Fruchart JC, De Geteire C, Delfly B, et al. Apolipoprotein A-I-containing particles and reverse cholesterol transport: evidence for connection between cholesterol efflux and atherosclerosis risk. Atherosclerosis. 1994; 110 (suppl): S35–S39.
    
34. Hill SA, McQueen MJ. Reverse cholesterol transport: a review of the process and its clinical implications. Clin Biochem. 1997; 30: 517–525.[Medline] [Order article via Infotrieve]
    
35. Barter PJ, Rye KA. Molecular mechanisms of reverse cholesterol transport. Curr Opin Lipidol. 1996; 7: 82–87.[Medline] [Order article via Infotrieve]
    
36. Castro G, Nihoul LP, Dengremont C, et al. Cholesterol efflux, lecithin-cholesterol acyltransferase activity, and pre-beta particle formation by serum from human apolipoprotein A-I and apolipoprotein A-I/apolipoprotein A-II transgenic mice consistent with the latter being less effective for reverse cholesterol transport. Biochemistry. 1997; 36: 2243–2249.[Medline] [Order article via Infotrieve]
    
37. Bruce C, Chouinard RA Jr, Tall AR. Plasma lipid transfer proteins, high-density lipoproteins, and reverse cholesterol transport. Annu Rev Nutr. 1998; 18: 297–330.[Medline] [Order article via Infotrieve]
    
38. Chiesa G, Parolini C, Canavesi M, et al. Human apolipoproteins A-I and A-II in cell cholesterol efflux: studies with transgenic mice. Arterioscler Thromb Vasc Biol. 1998; 18: 1417–1423.[Abstract/Free Full Text]
    
39. Rader DJ, Ikewaki K, Duverger N, et al. Very low high-density lipoproteins without coronary atherosclerosis. Lancet. 1993; 342: 1455–1458.[Medline] [Order article via Infotrieve]
    
40. Franceschini G, Sirtori CR, Capurso AD, et al. A-I_Milano apoprotein: decreased high density lipoprotein cholesterol levels with significant lipoprotein modifications and without clinical atherosclerosis in an Italian family. J Clin Invest. 1980; 66: 892–900.
    
41. Weisgraber KH, Bersot TP, Mahley RW, et al. A-I_Milano apoprotein: isolation and characterization of a cysteine-containing variant of the A-I apoprotein from human high density lipoproteins. J Clin Invest. 1980; 66: 901–907.
    
42. Franceschini G, Calabresi L, Chiesa G, et al. Increased cholesterol efflux potential of sera from ApoA-I_Milano carriers and transgenic mice. Arterioscler Thromb Vasc Biol. 1999; 19: 1257–1262.[Abstract/Free Full Text]
    
43. Bielicki JK, McCall MR, Stoltzfus LJ, et al. Evidence that apolipoprotein A-I_Milano has reduced capacity, compared with wild-type apolipoprotein A-I, to recruit membrane cholesterol. Arterioscler Thromb Vasc Biol. 1997; 17: 1637–1643.[Abstract/Free Full Text]
    
44. Kashyap ML. Basic considerations in the reversal of atherosclerosis: significance of high-density lipoprotein in stimulating reverse cholesterol transport. Am J Cardiol. 1989; 63: 56H–59H.[Medline] [Order article via Infotrieve]
    
45. Kashyap ML. Mechanistic studies of high-density lipoproteins. Am J Cardiol. 1998; 82: 42U–48U;discussion 85U–86U.[Medline] [Order article via Infotrieve]
    
46. Harper CR, Jacobson TA. New perspectives on the management of low levels of high-density lipoprotein cholesterol. Arch Intern Med. 1999; 159: 1049–1057.[Abstract/Free Full Text]
    
47. Mikhailidis DP, Wierzbicki AS. HDL-cholesterol and the treatment of coronary heart disease: contrasting effects of atorvastatin and simvastatin. Curr Med Res Opin. 2000; 16: 139–146.[Medline] [Order article via Infotrieve]
    
48. Crouse JR 3rd, Frohlich J, Ose L, et al. Effects of high doses of simvastatin and atorvastatin on high-density lipoprotein cholesterol and apolipoprotein A-I. Am J Cardiol. 1999; 83: 1476–1477, A7.[Medline] [Order article via Infotrieve]
    
49. Martin G, Duez H, Blanquart C, et al. Statin-induced inhibition of Rho-signaling pathway activates PPAR and induces HDL apoA-I. J Clin Invest. 2001; 107: 1423–1432.[Medline] [Order article via Infotrieve]
    
50. Okamoto H, Yonemori F, Wakitani K, et al. A cholesteryl ester transfer protein inhibitor attenuates atherosclerosis in rabbits. Nature. 2000; 406: 203–207.[Medline] [Order article via Infotrieve]
    
51. Barter P. CETP and atherosclerosis. Arterioscler Thromb Vasc Biol. 2000; 20: 2029–2031.[Free Full Text]
    
52. Rittershaus CW, Miller DP, Thomas LJ, et al. Vaccine-induced antibodies inhibit CETP activity in vivo and reduce aortic lesions in a rabbit model of atherosclerosis. Arterioscler Thromb Vasc Biol. 2000; 20: 2106–2112.[Abstract/Free Full Text]
    
53. Ameli S, Hultgardh-Nilsson A, Cercek B, et al. Recombinant apolipoprotein A-I_Milano reduces intimal thickening after balloon injury in hypercholesterolemic rabbits. Circulation. 1994; 90: 1935–1941.[Abstract/Free Full Text]
    
54. Shah PK, Nilsson J, Kaul S, et al. Effects of recombinant apolipoprotein A-I(Milano) on aortic atherosclerosis in apolipoprotein E-deficient mice. Circulation. 1998; 97: 780–785.[Abstract/Free Full Text]
    
55. Shah PK, Yano J, Reyes O, et al. High-dose recombinant apolipoprotein A-I_Milano mobilizes tissue cholesterol and rapidly reduces plaque lipid and macrophage content in apolipoprotein E-deficient mice. Circulation. 2001; 103: 3047–3050.[Abstract/Free Full Text]
    
56. Nilsson J, Dahlgren B, Ares M, et al. Lipoprotein-like phospholipid particles inhibit the smooth muscle cell cytotoxicity of lysophosphatidylcholine and platelet-activating factor. Arterioscler Thromb Vasc Biol. 1998; 18: 13–19.[Abstract/Free Full Text]
    
57. Dimayuga P, Zhu J, Oguchi S, et al. Reconstituted HDL containing human apolipoprotein A-1 reduces VCAM-1 expression and neointima formation following periadventitial cuff-induced carotid injury in apoE null mice. Biochem Biophys Res Commun. 1999; 264: 465–468.[Medline] [Order article via Infotrieve]
    
58. Simon DI, Dhen Z, Seifert P, et al. Decreased neointimal formation in Mac-1(-/-) mice reveals a role for inflammation in vascular repair after angioplasty. J Clin Invest. 2000; 105: 293–300.[Medline] [Order article via Infotrieve]
    
59. Nanjee MN, Crouse JR, King JM, et al. Effects of intravenous infusion of lipid-free apo A-I in humans. Arterioscler Thromb Vasc Biol. 1996; 16: 1203–1214.[Abstract/Free Full Text]
    
60. Nanjee MN, Doran JE, Lerch PG, et al. Acute effects of intravenous infusion of ApoA1/phosphatidylcholine discs on plasma lipoproteins in humans. Arterioscler Thromb Vasc Biol. 1999; 19: 979–989.[Abstract/Free Full Text]
    
61. Eriksson M, Carlson LA, Miettinen TA, et al. Stimulation of fecal steroid excretion after infusion of recombinant proapolipoprotein A-I: potential reverse cholesterol transport in humans. Circulation. 1999; 100: 594–598.[Abstract/Free Full Text]
    
62. Mendez AJ, Anantharamaiah GM, Segrest JP, et al. Synthetic amphipathic helical peptides that mimic apolipoprotein A-I in clearing cellular cholesterol. J Clin Invest. 1994; 94: 1698–1705.
    
63. Mishra VK, Palgunachari MN, Datta G, et al. Studies of synthetic peptides of human apolipoprotein A-I containing tandem amphipathic alpha-helixes. Biochemistry. 1998; 37: 10313–10324.[Medline] [Order article via Infotrieve]
    
64. Rodrigueza WV, Williams KJ, Rothblat GH, et al. Remodeling and shuttling: mechanisms for the synergistic effects between different acceptor particles in the mobilization of cellular cholesterol. Arterioscler Thromb Vasc Biol. 1997; 17: 383–393.[Abstract/Free Full Text]
    
65. Rodrigueza WV, Mazany KD, Essenburg AD, et al Large versus small unilamellar vesicles mediate reverse cholesterol transport in vivo into two distinct hepatic metabolic pools: implications for the treatment of atherosclerosis. Arterioscler Thromb Vasc Biol. 1997; 17: 2132–2139.[Abstract/Free Full Text]
    
66. Williams KJ, Scalia R, Mazany KD, et al. Rapid restoration of normal endothelial functions in genetically hyperlipidemic mice by a synthetic mediator of reverse lipid transport. Arterioscler Thromb Vasc Biol. 2000; 20: 1033–1039.[Abstract/Free Full Text]
    
67. Tangirala RK, Tsukamoto K, Chun SH, et al. Regression of atherosclerosis induced by liver-directed gene transfer of apolipoprotein A-I in mice. Circulation. 1999; 100: 1816–1822.[Abstract/Free Full Text]
    
68. Rader DJ. Gene therapy for atherosclerosis. Int J Clin Lab Res. 1997; 27: 35–43.[Medline] [Order article via Infotrieve]
    
69. Tsukamoto K, Hiester KG, Smith P, et al. Comparison of human apoA-I expression in mouse models of atherosclerosis after gene transfer using a second generation adenovirus. J Lipid Res. 1997; 38: 1869–1876.[Abstract]
    
70. Benoit P, Emmanuel F, Caillaud JM, et al. Somatic gene transfer of human ApoA-I inhibits atherosclerosis progression in mouse models. Circulation. 1999; 99: 105–110.[Abstract/Free Full Text]
    
71. Acton S, Rigotti A, Landschulz KT, et al. Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science. 1996; 271: 518–520.[Abstract]
    
72. Lawn RM, Wade DP, Garvin MR, et al. The Tangier disease gene product ABC1 controls the cellular apolipoprotein-mediated lipid removal pathway. J Clin Invest. 1999; 104: R25–R31.
    
73. Costet P, Luo Y, Wang N, et al. Sterol dependent transcativation of the human ABC I promoter by liver X receptor/retinoid X receptor. J Biol Chem. 2000; 275: 28240–28245.[Abstract/Free Full Text]
    
74. Schwartz K, Lawn R, Wade DP. ABC I gene expression and apo A-I mediated cholesterol efflux are regulated by LXR. Biochem Biophys Res Comm. 2000; 274: 794–802.[Medline] [Order article via Infotrieve]
    
75. Venketaswaran A, Laffitte BA, Joseph SB, et al. Control of cellular cholesterol efflux by nuclear oxysterol receptor LXR alpha. Proc Natl Acad Sci U S A. 2000; 97: 12097–12102.[Abstract/Free Full Text]
    
76. Repa JJ, Turley SD, Lobaccaro JA, et al. Regulation of absorption and ABC I-mediated efflux of cholesterol by RXR heterodimers. Science. 2000; 289: 1524–1529.[Abstract/Free Full Text]
    
77. Oliver WR, Shenk JL, Snaith MR et al. A selective PPAR- agonist promotes reverse cholesterol transport. Proc Natl Acad Sci U S A. 2001; 98: 5306–5311.[Abstract/Free Full Text]
    
78. Claudel T, Leibowitz MD, Fievet C et al. Reduction of atherosclerosis in apolipoprotein E knockout mice by activation of retinoid X receptor. Proc Natl Acad Sci U S A. 2001; 98: 2610–2615.[Abstract/Free Full Text]
    
79. Berge K, Tian H, Graf G, et al: Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science. 2000; 290: 1771–1775.[Abstract/Free Full Text]
    
80. Allayee H, Laffitte BA, Lusis AJ. An absorbing study of cholesterol. Science. 2000; 290: 1709–1711.[Free Full Text]
    

This article has been cited by other articles:

				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]

				J. S. Troutt, W. E. Alborn, M. K. Mosior, J. Dai, A. T. Murphy, T. P. Beyer, Y. Zhang, G. Cao, and R. J. Konrad An apolipoprotein A-I mimetic dose-dependently increases the formation of pre{beta}1 HDL in human plasma J. Lipid Res., March 1, 2008; 49(3): 581 - 587. [Abstract] [Full Text] [PDF]

				S. E. Nissen, J.-C. Tardif, S. J. Nicholls, J. H. Revkin, C. L. Shear, W. T. Duggan, W. Ruzyllo, W. B. Bachinsky, G. P. Lasala, E. M. Tuzcu, et al. Effect of Torcetrapib on the Progression of Coronary Atherosclerosis N. Engl. J. Med., March 29, 2007; 356(13): 1304 - 1316. [Abstract] [Full Text] [PDF]

				C. Mineo, H. Deguchi, J. H. Griffin, and P. W. Shaul Endothelial and Antithrombotic Actions of HDL Circ. Res., June 9, 2006; 98(11): 1352 - 1364. [Abstract] [Full Text] [PDF]

				D. Masson, J.-P. Pais de Barros, Z. Zak, T. Gautier, N. Le Guern, M. Assem, J. W. Chisholm, J. R. Paterniti Jr., and L. Lagrost Human apoA-I expression in CETP transgenic rats leads to lower levels of apoC-I in HDL and to magnification of CETP-mediated lipoprotein changes J. Lipid Res., February 1, 2006; 47(2): 356 - 365. [Abstract] [Full Text] [PDF]

				H. Yu, W. Zhang, P. G. Yancey, M. J. Koury, Y. Zhang, S. Fazio, and M. F. Linton Macrophage Apolipoprotein E Reduces Atherosclerosis and Prevents Premature Death in Apolipoprotein E and Scavenger Receptor-Class BI Double-Knockout Mice Arterioscler. Thromb. Vasc. Biol., January 1, 2006; 26(1): 150 - 156. [Abstract] [Full Text] [PDF]

				V. Fuster, P. R. Moreno, Z. A. Fayad, R. Corti, and J. J. Badimon Atherothrombosis and High-Risk Plaque: Part I: Evolving Concepts J. Am. Coll. Cardiol., September 20, 2005; 46(6): 937 - 954. [Abstract] [Full Text] [PDF]

				H. Gupta, L. Dai, G. Datta, D. W. Garber, H. Grenett, Y. Li, V. Mishra, M. N. Palgunachari, S. Handattu, S. H. Gianturco, et al. Inhibition of Lipopolysaccharide-Induced Inflammatory Responses by an Apolipoprotein AI Mimetic Peptide Circ. Res., August 5, 2005; 97(3): 236 - 243. [Abstract] [Full Text] [PDF]

				K. J. Williams and I. Tabas Lipoprotein Retention--and Clues for Atheroma Regression Arterioscler. Thromb. Vasc. Biol., August 1, 2005; 25(8): 1536 - 1540. [Abstract] [Full Text] [PDF]

				J. S. Forrester, R. Makkar, and P.K. Shah Increasing High-Density Lipoprotein Cholesterol in Dyslipidemia by Cholesteryl Ester Transfer Protein Inhibition: An Update for Clinicians Circulation, April 12, 2005; 111(14): 1847 - 1854. [Abstract] [Full Text] [PDF]

				X. Li, K.-Y. Chyu, J. R. F. Neto, J. Yano, N. Nathwani, C. Ferreira, P. C. Dimayuga, B. Cercek, S. Kaul, and P. K. Shah Differential Effects of Apolipoprotein A-I-Mimetic Peptide on Evolving and Established Atherosclerosis in Apolipoprotein E-Null Mice Circulation, September 21, 2004; 110(12): 1701 - 1705. [Abstract] [Full Text] [PDF]

				S. C. Fagan, D. C. Hess, E. J. Hohnadel, D. M. Pollock, and A. Ergul Targets for Vascular Protection After Acute Ischemic Stroke Stroke, September 1, 2004; 35(9): 2220 - 2225. [Abstract] [Full Text] [PDF]

				D. J. Rader High-Density Lipoproteins as an Emerging Therapeutic Target for Atherosclerosis JAMA, November 5, 2003; 290(17): 2322 - 2324. [Full Text] [PDF]

				J. Ou, Z. Ou, D. W. Jones, S. Holzhauer, O. A. Hatoum, A. W. Ackerman, D. W. Weihrauch, D. D. Gutterman, K. Guice, K. T. Oldham, et al. L-4F, an Apolipoprotein A-1 Mimetic, Dramatically Improves Vasodilation in Hypercholesterolemia and Sickle Cell Disease Circulation, May 13, 2003; 107(18): 2337 - 2341. [Abstract] [Full Text] [PDF]

				P. K. Shah Mechanisms of plaque vulnerability and rupture J. Am. Coll. Cardiol., February 19, 2003; 41(4_Suppl_S): 15S - 22S. [Abstract] [Full Text] [PDF]

				P. K. Shah Low-Density Lipoprotein Lowering and Atherosclerosis Progression: Does More Mean Less? Circulation, October 15, 2002; 106(16): 2039 - 2040. [Full Text] [PDF]

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire