当前位置: 首页 > 医学版 > 期刊论文 > 内科学 > 动脉硬化血栓血管生物学 > 2005年 > 第8期 > 正文
编号:11257635
Lipoprotein Retention—and Clues for Atheroma Regression
     From the Dorrance H. Hamilton Research Laboratories, Division of Endocrinology, Diabetes, and Metabolic Diseases, Department of Medicine (K.J.W.), Jefferson Medical College of Thomas Jefferson University, Philadelphia, Penn; and the Departments of Medicine, Anatomy & Cell Biology, and Physiology & Cellular Biophysics (I.T.), Columbia University, New York, NY.

    Correspondence to Kevin Jon Williams, Department of Medicine, Thomas Jefferson University, 1020 Locust Street, Suite 348, Philadelphia, PA 19107. E-mail K_Williams@mail.jci.tju.edu

    Abstract

    Subendothelial retention of apoB-lipoproteins is the key initiating event in atherosclerosis, provoking a cascade of pathogenic responses. Dissection of the molecular participants provides fresh insight into how this major killer might be reversed. Efflux of harmful lipids derived from retained lipoproteins may be crucial in promoting beneficial remodeling of lesions.

    The pathogenic mechanisms responsible for atherosclerosis have been the subject of considerable debate over the decades (reviewed in references 1–5). It is more than a theoretical concern. Despite the clinical successes of current plasma lipid-lowering strategies, such strategies fail to stop most cardiovascular events.6–8 Pathogenic understanding is needed to guide the development of new strategies to fill this therapeutic void.

    See page 1678

    A central role for cholesterol-rich apoB lipoproteins is now clear, but there has been a long controversy regarding triglyceride-rich particles (TRPs) and atherogenesis. Epidemiologic studies have shown a link, although the direct importance of this link has been clouded by the common association of hypertriglyceridemia with additional atherogenic factors, particularly insulin resistance, hypertension, low plasma high-density lipoprotein (HDL) concentrations, and the presence of small dense low-density lipoproteins (LDL). Moreton9 and Zilversmit10 advocated a direct role for post-prandial TRPs, which can carry a substantial amount of cholesterol.11 Moreover, despite their size, TRPs penetrate into the arterial wall and become retained there.12,13 Extracellular matrix is key to this retention, chiefly involving arterial proteoglycans,14–16 and proteoglycan-binding sequences were identified in apoB100 and apoB48 and shown to be pathogenically essential in the initiation of atherogenesis in vivo, though mainly for LDL.17

    In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, ??rni et al18 provide fresh insight into the mechanisms by which TRPs could be retained in the arterial wall and thereby contribute to atherogenesis. Although the affinity of small very low–density lipoproteins (sVLDL) and intermediate-density lipoproteins (IDL) for arterial proteoglycans is lower than that of LDL, sphingomyelinase, an enzyme secreted by endothelial cells into the extracellular mileu of the arterial wall,19 causes these particles to aggregate and fuse.18 Once this occurs, their affinity for matrix increases. If similar events occur during atherogenesis, the movement of these particles would be sterically hindered as well, and their egress out of the wall would become unlikely. Moreover, sphingomyelinase-induced aggregation of TRPs increases their ability to load macrophages with cholesterol.20 Sphingomyelinase-induced aggregation of LDL and Lp(a) also increases their affinity for proteoglycans and their ability to load macrophages with cholesterol.21,22 Although LDL retention can be increased by several arterial-wall enzymes, ??rni et al found that sphingomyelinase is particularly important for these TRPs.18

    Can anything helpful be done with this and other discoveries related to the pathogenesis of atherosclerosis? Large, prospective, randomized trials of antibacterials23–25 and of vitamin E alone or in combination with other antioxidants26,27 failed to show benefit in human atherosclerotic vascular disease, although it is possible that future studies with other types of these agents could be successful. A shared etiology with cancer was implied by the monoclonal theory of atherosclerosis,1,28–31 but antineoplastic agents would be impractical in this setting, and the apparent monoclonality of atheromata may arise simply because of unexpectedly large X-inactivation patches within normal human arteries.32

    This leaves the response-to-retention theory (reviewed in references 3 and 17), which is the focus of the article by ??rni et al, and the inflammation hypothesis,33,34 which was put forth as a descendant of the response-to-injury model35 but also has roots in Virchow’s earlier concept of "endarteritis deformans."2,4 The response-to-retention and inflammation theories are intellectually compatible, in that retained and modified lipoproteins within the arterial wall are now generally regarded as the essential stimulus for the activation of endothelium and the recruitment of macrophages, T-cells, and mast cells, as well as a number of important responses that are not inflammatory, such as in-migration of smooth muscle cells.33,34,36 Hyperbetalipoproteinemia, which quickly leads to lipoprotein retention at atherosclerosis-prone sites,37–40 provides a powerful stimulus that acts synergistically with local, preexisting turbulent flow to turn on endothelial NF-B and induce cell-adhesion molecule display, before macrophage infiltration.41,42 Local enzymatic digestion of these retained lipoproteins, in addition to causing the physical changes documented by ??rni et al, triggers the release of proinflammatory products,43 and it is tempting to speculate that the set of molecules released from retained TRPs might differ from the ones generated from LDL. Macrophages subsequently recruited to the developing lesion secrete molecules, including lipoprotein lipase44 and additional sphingomyelinase,45 that promote further lipoprotein retention, modification, and release of biologically active byproducts. Nonenzymatic modifications are likely to contribute to these processes as well.46

    Of particular note is the recent discovery of lipoprotein-derived lipids that block macrophage emigration, thereby forcing these cells into an abnormal state of persistence within the lesion.47 Moreover, intracellular accumulation of lipoprotein-derived unesterified cholesterol can lead to macrophage apoptosis, which, in the absence of phagocytic clearance, can contribute to necrotic core formation.48,49 Thus, retained and modified lipoproteins cause significant derangements of macrophage function, and hence of the inflammatory response. These derangements may help explain why direct antiinflammatory therapeutic agents have not proven beneficial in human atherosclerosis to date,33,50 although new approaches are being explored.34,51

    If arterial retention of apoB-lipoproteins is the essential pathophysiologic process in atherosclerosis, it makes the clinical successes of conventional lipid lowering easy to understand. Nevertheless, as noted above, this approach has had limited benefits using our current set of hypolipidemic agents in pre-established arterial disease. One answer may be to push plasma apoB-lipoprotein levels even lower,52 and combinations of old and new agents might make this possible while keeping side-effects under control, although this still needs additional testing.53 Another is to interfere with specific molecular participants in lipoprotein retention and modification. Agents to compete with direct apoB–proteoglycan interactions,3,54 though ingenious, are unlikely to be practical owing to the stoichiometry, and they may lose efficacy as additional molecular processes that facilitate lipoprotein retention come into play during lesion progression.3,44,55,56 Another strategy related to the work of ??rni et al18 would be to interfere with the hydrolysis of lipoproteins by sphingomyelinase. High lipoprotein sphingomyelin content is an independent risk factor for atherosclerosis in humans,57 and inhibition of sphingomyelin synthesis was recently reported to slow arterial lesion development in apoE-null mice out of proportion to its lipid-lowering effect.58,59 Similarly, genetic targeting of sphingomyelinase in apoE-null mice is associated with a marked reduction in early lesion development60 (Devlin C, Leventhal A, Kuriakose G, Williams KJ, Tabas I, unpublished data, July 2003 to March 2005).

    If retained and modified lipoproteins are the root cause of this disease, then reaching into the arterial wall to remove the offending material should be beneficial, like pulling out a troublesome splinter.5,6,61,62 Although much progress has occurred recently in our understanding of how apoA-I, HDL, and HDL-like particles mobilize lipids from loaded cells,63 little attention has been paid to extracellular lipid deposits, which is exactly what ??rni et al created in vitro. Such deposits have long been recognized in human plaques and consist of a variety of components, including retained and aggregated lipoproteins, cholesterol-rich vesicular structures, cholesterol crystals, and debris from necrotic cells.64–67 This material could be phagocytozed by macrophages, which under healthy conditions might apoptose safely in situ,68–70 actively exit the plaque,47 or release their extra lipid to apoA-I and HDL via passive diffusion, ABC transporters, and SR-BI63 (see the Figure). In fact, several strategies designed to enhance cellular lipid efflux are currently in human clinical trials,71–73 and other approaches are being developed.6,63,74–76 Under the right circumstances, even non-lipid components can improve, including calcification, fibrosis, and tissue factor expression.77–82

    Retention, responses, and regression. Retention (yellow arrows): ApoB-lipoproteins (LP) continually enter and exit the arterial wall, but some particles adhere to the local matrix long enough to become modified by enzymes and other factors, resulting in essentially irreversible retention. LDL has a major role in these crucial initiating steps. Despite their size, IDL and small VLDL (sVLDL) also participate, particularly through the action of sphingomyelinase (SMase), which causes these particles to aggregate, thereby increasing their affinity for proteoglycans (PG) in the matrix. Responses (red arrows): Retained and modified lipoproteins release biologically active byproducts that activate the endothelium and attract monocyte/macrophages and smooth muscle cells. Aggregated lipoproteins in particular are avidly phagocytozed by macrophages, which become foam cells. Other lipoprotein-derived molecules block the normal emigration of foam cells from the developing lesion, so that the lipid that has accumulated cannot be removed through cellular trafficking. Macrophages that persist in the lesion secrete a number of important molecules, including matrix metalloproteinases (MMPs), which weaken the fibrous cap, and tissue factor (TF), a potent procoagulant that is released on plaque rupture. Many of these macrophages eventually accumulate large amounts of lipoprotein-derived unesterified cholesterol (UC) and die by apoptosis. In the absence of effective phagocytosis, the cells become secondarily necrotic. This cellular debris, together with extracellular lipids, leads to necrotic core formation. Lipoproteins and lipoprotein-loaded cells also contribute to the appearance of UC-rich vesicles and crystals. Regression (green arrows): Naturally occurring acceptors, apoA-I and HDL, extract unesterified cholesterol and other molecules from lesional cells via aqueous diffusion (AqD), ABC transporters (ABC), and the scavenger receptor-BI (SR-BI). Artificial acceptors rich in phosphatidylcholine (PC), such as liposomes or apoA-I/PC complexes, mobilize material from extracellular deposits, as well as from apoA-I and HDL. Under the proper circumstances, substantial remodeling of the plaque can occur, including efflux of harmful or superfluous lipids, phagocytosis and digestion of debris, and the normal emigration of macrophages from the arterial wall.

    But in the human disease, much of the retained and modified material remains extracellular. One recent study using insoluble extracts from human plaques indicated that apoA-I and HDL are surprisingly inert at mobilizing non-cellular lipid; only acceptor particles particularly rich in phosphatidylcholine (PC) were effective.83 The relevance in vivo of this provocative observation remains to be seen, although it suggests that the participation of active phagocytic cells or the administration of exogenous PC-rich acceptors might be helpful, especially given that phagocytes63 and artificial acceptors61,83,84 can cooperate with endogenous HDL and its components in the mobilization of lipids for disposal. Consistent with this idea, artificial PC-rich particles have been shown in vivo to mediate "reverse" lipid transport from the periphery to the liver,85–89 suppress inflammatory responses in dysfunctional vessels during hyperbetalipoproteinemia,90,91 and shrink arterial lesions both in animals61,92–94 and, in one small trial, in humans.72 These results are of current interest, given our recognition of the role of lipid-rich vulnerable plaques in acute coronary events.95,96

    Everything that we identify, from general theories of pathogenesis to specific molecular participants, must eventually pass muster in the authentic human disease. Regrettably, as shown by the recently completed clinical trials,23–27 many scientific discoveries are not readily put to use. By this standard, the coming few years will be a crucial test of the idea that lipoprotein retention and its consequences can be reversed. As atherosclerosis continues to grow as a worldwide killer, we must apply knowledge about its pathogenesis toward improving the lives of our patients and their families, despite the nearly insurmountable obstacles of translating discoveries into practice.97,98

    References

    Benditt EP. The origin of atherosclerosis. Sci Am. 1977; 236: 74–85.

    Capron L. Pathogenie de l’atherosclerose: mises a jour des trois theories dominantes. Ann Cardiol D’Angeiolog. 1989; 38: 631–634.

    Williams KJ, Tabas I. The response-to-retention hypothesis of early atherogenesis. Arterioscler Thromb Vasc Biol. 1995; 15: 551–561.

    Ventura HO. Profiles in cardiology. Rudolph Virchow and cellular pathology. Clin Cardiol. 2000; 23: 550–552.

    Williams KJ, Fisher EA. Oxidation, lipoproteins, and atherosclerosis: which is wrong, the antioxidants or the theory? Curr Opin Clin Nutr Metab Care. 2005; 8: 139–146.

    Shah PK, Kaul S, Nilsson J, Cercek B. Exploiting the vascular protective effects of high-density lipoprotein and its apolipoproteins: an idea whose time for testing is coming, part II. Circulation. 2001; 104: 2498–2502.

    Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O’Brien E, Ostergren J. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003; 361: 1149–1158.

    LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, Gotto AM, Greten H, Kastelein JJ, Shepherd J, Wenger NK. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005; 352: 1425–1435.

    Moreton JR. Atherosclerosis and alimentary hyperlipemia. Science. 1947; 106: 190–191.

    Zilversmit DB. Atherogenesis: a postprandial phenomenon. Circulation. 1979; 60: 473–485.

    Bj?rkegren J, Boquist S, Samneg?rd A, Lundman P, Tornvall P, Ericsson C-G, Hamsten A. Accumulation of apolipoprotein C-I-rich and cholesterol-rich VLDL remnants during exaggerated postprandial triglyceridemia in normolipidemic patients with coronary artery disease. Circulation. 2000; 101: 227–230.

    Rapp JH, Lespine A, Hamilton RL, Colyvas N, Chaumeton AH, Tweedie-Hardman J, Kotite L, Kunitake ST, Havel RJ, Kane JP. Triglyceride-rich lipoproteins isolated by selected-affinity anti-apolipoprotein B immunosorption from human atherosclerotic plaque. Arterioscler Thromb. 1994; 14: 1767–1774.

    Nordestgaard BG. The vascular endothelial barrier: selective retention of lipoproteins. Curr Opin Lipidol. 1996; 7: 269–273.

    Hurt-Camejo E, Olsson U, Wiklund O, Bondjers G, Camejo G. Cellular consequences of the association of apoB lipoproteins with proteoglycans. Potential contribution to atherogenesis. Arterioscler Thromb Vasc Biol. 1997; 17: 1011–1017.

    O’Brien KD, Olin KL, Alpers CE, Chiu W, Ferguson M, Hudkins K, Wight TN, Chait A. Comparison of apolipoprotein and proteoglycan deposits in human coronary atherosclerotic plaques: colocalization of biglycan with apolipoproteins. Circulation. 1998; 98: 519–527.

    Vikramadithyan RK, Kako Y, Chen G, Hu Y, Arikawa-Hirasawa E, Yamada Y, Goldberg IJ. Atherosclerosis in perlecan heterozygous mice. J Lipid Res. 2004; 45: 1806–1812.

    Sk?lén K, Gustafsson M, Rydberg EK, Hultén LM, Wiklund O, Innerarity TL, Borén J. Subendothelial retention of atherogenic lipoproteins in early atherosclerosis. Nature. 2002; 417: 750–754.

    ??rni K, Posio P, Ala-Korpela M, Jauhiainen M, Kovanen P. Sphingomyelinase induces aggregation and fusion of small VLDL and IDL particles and increases their retention to human arterial proteoglycans Arterioscler Thromb Vasc Biol. 2005; 25: 1678–1683.

    Marathe S, Kuriakose G, Williams KJ, Tabas I. Sphingomyelinase, an enzyme implicated in atherogenesis, is present in atherosclerotic lesions and binds to specific components of the subendothelial extracellular matrix. Arterioscler Thromb Vasc Biol. 1999; 19: 2648–2658.

    Marathe S, Choi Y, Leventhal AR, Tabas I. Sphingomyelinase converts lipoproteins from apolipoprotein E knockout mice into potent inducers of macrophage foam cell formation. Arterioscler Thromb Vasc Biol. 2000; 20: 2607–2613.

    Tabas I, Li Y, Brocia RW, Xu SW, Swenson TL, Williams KJ. Lipoprotein lipase and sphingomyelinase synergistically enhance the association of atherogenic lipoproteins with smooth muscle cells and extracellular matrix. A possible mechanism for low density lipoprotein and lipoprotein(a) retention and macrophage foam cell formation. J Biol Chem. 1993; 268: 20419–20432.

    ??rni K, Hakala JK, Annila A, Ala-Korpela M, Kovanen PT. Sphingomyelinase induces aggregation and fusion, but phospholipase A2 only aggregation, of low density lipoprotein (LDL) particles. Two distinct mechanisms leading to increased binding strength of LDL to human aortic proteoglycans. J Biol Chem. 1998; 273: 29127–29134.

    O’Connor CM, Dunne MW, Pfeffer MA, Muhlestein JB, Yao L, Gupta S, Benner RJ, Fisher MR, Cook TD. Azithromycin for the secondary prevention of coronary heart disease events: the WIZARD study: a randomized controlled trial. JAMA. 2003; 290: 1459–1466.

    Grayston JT, Kronmal RA, Jackson LA, Parisi AF, Muhlestein JB, Cohen JD, Rogers WJ, Crouse JR, Borrowdale SL, Schron E, Knirsch C. Azithromycin for the secondary prevention of coronary events. N Engl J Med. 2005; 352: 1637–1645.

    Cannon CP, Braunwald E, McCabe CH, Grayston JT, Muhlestein B, Giugliano RP, Cairns R, Skene AM. Antibiotic treatment of Chlamydia pneumoniae after acute coronary syndrome. N Engl J Med. 2005; 352: 1646–1654.

    Stocker R, Keaney JF Jr. Role of oxidative modifications in atherosclerosis. Physiol Rev. 2004; 84: 1381–1478.

    Miller ER,3rd, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-Analysis: High-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2005; 142: 37–46.

    Pearson TA, Dilman J, Williams KJ, Wolff JA, Adams R, Solez K, Heptinstall RH, Malmros H, Sternby N. Clonal characteristics of experimentally induced "atherosclerotic" lesions in the hybrid hare. Science. 1979; 206: 1423–1425.

    Scott J. Oncogenes in atherosclerosis. Nature. 1987; 325: 574–575.

    Markowitz SD. Atherosclerosis, just another cancer? J Clin Invest. 1997; 100: 2143–2145.

    Ross JS, Stagliano NE, Donovan MJ, Breitbart RE, Ginsburg GS. Atherosclerosis and cancer: common molecular pathways of disease development and progression. Ann N Y Acad Sci. 2001; 947: 271–293.

    Murry CE, Gipaya CT, Bartosek T, Benditt EP, Schwartz SM. Monoclonality of smooth muscle cells in human atherosclerosis. Am J Pathol. 1997; 151: 697–705.

    Nilsson J, Hansson GK, Shah PK. Immunomodulation of atherosclerosis: implications for vaccine development. Arterioscler Thromb Vasc Biol. 2005; 25: 18–28.

    Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005; 352: 1685–1695.

    Ross R, Glomset J, Harker L. Response to injury and atherogenesis. Am J Pathol. 1977; 86: 675–684.

    Williams KJ, Tabas I. Atherosclerosis and inflammation. Science. 2002; 297: 521–522.

    Bragdon JH. Transfusion transfer of atherosclerosis. Circulation. 1951; 4: 466.Abstract.

    Bragdon JH, Boyle E, Havel RJ. Human serum lipoproteins. II. Some effects of their intravenous injection in rats. J Lab Clin Med. 1956; 48: 43–50.

    Schwenke DC, Carew TE. Initiation of atherosclerotic lesions in cholesterol-fed rabbits. II. Selective retention of LDL vs. selective increases in LDL permeability in susceptible sites of arteries. Arteriosclerosis. 1989; 9: 908–918.

    Nievelstein PFEM, Fogelman AM, Mottino G, Frank JS. Lipid accumulation in rabbit aortic intima 2 hours after bolus infusion of low density lipoprotein. A deep-etch and immunolocalization study of ultrarapidly frozen tissue. Arterioscler Thromb. 1991; 11: 1795–1805.

    Hajra L, Evans AI, Chen M, Hyduk SJ, Collins T, Cybulsky MI. The NF-kappa B signal transduction pathway in aortic endothelial cells is primed for activation in regions predisposed to atherosclerotic lesion formation. Proc Natl Acad Sci U S A. 2000; 97: 9052–9057.

    Orr AW, Sanders JM, Bevard M, Coleman E, Sarembock IJ, Schwartz MA. The subendothelial extracellular matrix modulates NF-kappa-B activation by flow: a potential role in atherosclerosis. J Cell Biol. 2005; 169: 191–202.

    Hurt-Camejo E, Camejo G, Peilot H, ??rni K, Kovanen P. Phospholipase A2 in vascular disease. Circ Res. 2001; 89: 298–304.

    Pentik?inen MO, Oksjoki R, ??rni K, Kovanen PT. Lipoprotein lipase in the arterial wall: linking LDL to the arterial extracellular matrix and much more. Arterioscler Thromb Vasc Biol. 2002; 22: 211–217.

    Schissel SL, Schuchman EH, Williams KJ, Tabas I. Zn2+-stimulated sphingomyelinase is secreted by many cell types and is a product of the acid sphingomyelinase gene. J Biol Chem. 1996; 271: 18431–18436.

    Medeiros LA, Khan T, El Khoury JB, Pham CL, Hatters DM, Howlett GJ, Lopez R, O’Brien KD, Moore KJ. Fibrillar amyloid protein present in atheroma activates CD36 signal transduction. J Biol Chem. 2004; 279: 10643–10648.

    Llodrá J, Angeli V, Liu J, Trogan E, Fisher EA, Randolph GJ. Emigration of monocyte-derived cells from atherosclerotic lesions characterizes regressive, but not progressive, plaques. Proc Natl Acad Sci U S A. 2004; 101: 11779–11784.

    Feng B, Yao PM, Li Y, Devlin CM, Zhang D, Harding HP, Sweeney M, Rong JX, Kuriakose G, Fisher EA, Marks AR, Ron D, Tabas I. The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages. Nat Cell Biol. 2003; 5: 781–792.

    Feng B, Zhang D, Kuriakose G, Devlin CM, Kockx M, Tabas I. Niemann-Pick C heterozygosity confers resistance to lesional necrosis and macrophage apoptosis in murine atherosclerosis. Proc Natl Acad Sci U S A. 2003; 100: 10423–10428.

    Ulbrich H, Eriksson EE, Lindbom L. Leukocyte and endothelial cell adhesion molecules as targets for therapeutic interventions in inflammatory disease. Trends Pharmacol Sci. 2003; 24: 640–647.

    Tardif JC. Antioxidants and atherosclerosis: emerging drug therapies. Curr Atheroscler Rep. 2005; 7: 71–77.

    Safety of aggressive statin therapy. Med Lett Drugs Ther. 2004; 46: 93–95.

    Pitt B. Low-density lipoprotein cholesterol in patients with stable coronary heart disease–is it time to shift our goals? N Engl J Med. 2005; 352: 1483–1484.

    Innerarity T, Boren J. Methods and tools for identifying compounds which modulate atherosclerosis by impacting LDL-proteoglycan binding. United States of America Patent # 6,579,682, assigned to The Regents of University of California; issued 17 June 2003.

    Gustafsson M. Retention of atherogenic lipoproteins in atherogenesis. Doctoral Thesis for the Degree of Doctor of Philosophy, Wallenberglaboratoriet f?r hj?rtsk?rlforskning, Sahlgrenska akademin vid G?teborgs Universitet, G?teborg, Sverige; defended 3 December 2004.

    O’Brien KD, McDonald TO, Kunjathoor V, Eng K, Knopp EA, Lewis K, Lopez R, Kirk EA, Chait A, Wight TN, deBeer FC, LeBoeuf RC. Serum amyloid A and lipoprotein retention in murine models of atherosclerosis. Arterioscler Thromb Vasc Biol. 2005; 25: 785–790.

    Jiang XC, Paultre F, Pearson TA, Reed RG, Francis CK, Lin M, Berglund L, Tall AR. Plasma sphingomyelin level as a risk factor for coronary artery disease. Arterioscler Thromb Vasc Biol. 2000; 20: 2614–2618.

    Park TS, Panek RL, Mueller SB, Hanselman JC, Rosebury WS, Robertson AW, Kindt EK, Homan R, Karathanasis SK, Rekhter MD. Inhibition of sphingomyelin synthesis reduces atherogenesis in apolipoprotein E-knockout mice. Circulation. 2004; 110: 3465–3471.

    Hojjati MR, Li Z, Zhou H, Tang S, Huan C, Ooi E, Lu S, Jiang XC. Effect of myriocin on plasma sphingolipid metabolism and atherosclerosis in apoE-deficient mice. J Biol Chem. 2005; 280: 10284–10289.

    Marathe S, Tribble DL, Kuriakose G, La Belle M, Chu BM, Gong EL, Johns A, Williams KJ, Tabas I. Sphingomyelinase (SMase) transgenic & knockout mice: direct evidence that SMase is atherogenic in vivo. Circulation. 1999; 100 (suppl.): I-695.Abstract.

    Williams KJ, Werth VP, Wolff JA. Intravenously administered lecithin liposomes: a synthetic antiatherogenic lipid particle. Perspect Biol Med. 1984; 27: 417–431.

    Spady DK. Reverse cholesterol transport and atherosclerosis regression. Circulation. 1999; 100: 576–578.

    Tall AR, Costet P, Wang N. Regulation and mechanisms of macrophage cholesterol efflux. J Clin Invest. 2002; 110: 899–904.

    Hoff HF, Gaubatz JW. Ultrastructural localization of plasma lipoproteins in human intracranial arteries. Virchows Arch A Pathol Anat Histol. 1975; 369: 111–121.

    Chao FF, Amende LM, Blanchette-Mackie EJ, Skarlatos SI, Gamble W, Resau JH, Mergner WT, Kruth HS. Unesterified cholesterol-rich lipid particles in atherosclerotic lesions of human and rabbit aortas. Am J Pathol. 1988; 131: 73–83.

    Guyton JR, Klemp KF. Development of the lipid-rich core in human atherosclerosis. Arterioscler Thromb Vasc Biol. 1996; 16: 4–11.

    Stary HC, Chandler AB, Dinsmore RE, Fuster V, Glagov S, Insull W Jr, Rosenfeld ME, Schwartz CJ, Wagner WD, Wissler RW. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation. 1995; 92: 1355–1374.

    Liu J, Thewke DP, Su YR, Linton MF, Fazio S, Sinensky MS. Reduced macrophage apoptosis is associated with accelerated atherosclerosis in low-density lipoprotein receptor-null mice. Arterioscler Thromb Vasc Biol. 2005; 25: 174–179.

    Arai S, Shelton JM, Chen M, Bradley MN, Castrillo A, Bookout AL, Mak PA, Edwards PA, Mangelsdorf DJ, Tontonoz P, Miyazaki T. A role for the apoptosis inhibitory factor AIM/Sp-alpha/Api6 in atherosclerosis development. Cell Metab. 2005; 1: 201–213.

    Schrijvers DM, De Meyer GRY, Kockx MM, Herman AG, Martinet W. Phagocytosis of apoptotic cells by macrophages is impaired in atherosclerosis. Arterioscler Thromb Vasc Biol. 2005; 25: 1256–1261.

    Rader DJ, Rodrigueza WV, Lalwani ND, Valiquet TR. Infusion of large unilamellar vesicles (ETC-588) mobilize unesterified cholesterol in a dose-dependent fashion in healthy volunteers. Arterioscler Thromb Vasc Biol. 2002; 22: a-53.Abstract.

    Nissen SE, Tsunoda T, Tuzcu EM, Schoenhagen P, Cooper CJ, Yasin M, Eaton GM, Lauer MA, Sheldon WS, Grines CL, Halpern S, Crowe T, Blankenship JC, Kerensky R. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA. 2003; 290: 2292–2300.

    Brousseau ME, Diffenderfer MR, Millar JS, Nartsupha C, Asztalos BF, Welty FK, Wolfe ML, Rudling M, Bjorkhem I, Angelin B, Mancuso JP, Digenio AG, Rader DJ, Schaefer EJ. Effects of cholesteryl ester transfer protein inhibition on high-density lipoprotein subspecies, apolipoprotein A-I metabolism, and fecal sterol excretion. Arterioscler Thromb Vasc Biol. 2005; 25: 1057–1064.

    Brewer HB Jr, Alaupovic P, Kostner G, Asztalos B, Schaefer E, Rothblat G, Akeefe H, Conner A, Perlman T, Kunas G, Bellotti M. Selective plasma HDL delipidation and reinfusion: a unique new approach for acute HDL therapy in the treatment of cardiovascular disease. Circulation. 2004; 110 (suppl): III-51–III-52.Abstract.

    Li X, Chyu KY, Neto JR, Yano J, Nathwani N, Ferreira C, Dimayuga PC, Cercek B, Kaul S, Shah PK. Differential effects of apolipoprotein A-I-mimetic peptide on evolving and established atherosclerosis in apolipoprotein E-null mice. Circulation. 2004; 110: 1701–1705.

    Navab M, Anantharamaiah GM, Reddy ST, Hama S, Hough G, Grijalva VR, Yu N, Ansell BJ, Datta G, Garber DW, Fogelman AM. Apolipoprotein A-I mimetic peptides. Arterioscler Thromb Vasc Biol. 2005; 25: 1325–1331.

    Armstrong ML. Evidence of regression of atherosclerosis in primates and man. Postgrad Med J. 1976; 52: 456–461.

    Wissler RW. Current status of regression studies. Atheroscler Rev. 1978; 3: 213–229.

    Blankenhorn DH, Hodis HN. George Lyman Duff Memorial Lecture. Arterial imaging and atherosclerosis reversal. Arterioscler Thromb. 1994; 14: 177–192.

    Callister TQ, Raggi P, Cooil B, Lippolis NJ, Russo DJ. Effect of HMG-CoA reductase inhibitors on coronary artery disease as assessed by electron-beam computed tomography. N Engl J Med. 1998; 339: 1972–1978.

    Aikawa M, Libby P. Lipid lowering reduces proteolytic and prothrombotic potential in rabbit atheroma. Ann N Y Acad Sci. 2000; 902: 140–152.

    Reis ED, Li J, Fayad ZA, Rong JX, Hansoty D, Aguinaldo JG, Fallon JT, Fisher EA. Dramatic remodeling of advanced atherosclerotic plaques of the apolipoprotein E-deficient mouse in a novel transplantation model. J Vasc Surg. 2001; 34: 541–547.

    Chung BH, Franklin F, Liang P, Doran S, Cho BH, Curcio CA. Phosphatidylcholine-rich acceptors, but not native HDL or its apolipoproteins, mobilize cholesterol from cholesterol-rich insoluble components of human atherosclerotic plaques. Biochim Biophys Acta. 2005; 1733: 76–89.

    Rodrigueza WV, Williams KJ, Rothblat GH, Phillips MC. 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.

    Williams KJ, Vallabhajosula S, Rahman IU, Donnelly TM, Parker TS, Weinrauch M, Goldsmith SJ. Low density lipoprotein receptor-independent hepatic uptake of a synthetic, cholesterol-scavenging lipoprotein: implications for the treatment of receptor-deficient atherosclerosis. Proc Natl Acad Sci U S A. 1988; 85: 242–246.

    Rodrigueza WV, Mazany KD, Essenburg AD, Pape ME, Rea TJ, Bisgaier CL, Williams KJ. 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.

    Eriksson M, Carlson LA, Miettinen TA, Angelin B. Stimulation of fecal steroid excretion after infusion of recombinant proapolipoprotein A-I: potential reverse cholesterol transport in humans. Circulation. 1999; 100: 594–598.

    Alam K, Meidell RS, Spady DK. Effect of up-regulating individual steps in the reverse cholesterol transport pathway on reverse cholesterol transport in normolipidemic mice. J Biol Chem. 2001; 276: 15641–15649.

    Nanjee MN, Cooke CJ, Garvin R, Semeria F, Lewis G, Olszewski WL, Miller NE. Intravenous apoA-I/lecithin discs increase pre-?-HDL concentration in tissue fluid and stimulate reverse cholesterol transport in humans. J Lipid Res. 2001; 42: 1586–1593.

    Williams KJ, Scalia R, Mazany KD, Rodrigueza WV, Lefer AM. 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.

    Kaul S, Coin B, Hedayiti A, Yano J, Cercek B, Chyu KY, Shah PK. Rapid reversal of endothelial dysfunction in hypercholesterolemic apolipoprotein E-null mice by recombinant apolipoprotein A-IMilano-phospholipid complex. J Am Coll Cardiol. 2004; 44: 1311–1319.

    Friedman M, Byers SO, Rosenman RH. Resolution of aortic atherosclerotic infiltration in the rabbit by phosphatide infusion. Proc Soc Exp Biol Med. 1957; 95: 586–588.

    Rodrigueza WV, Klimuk SK, Pritchard PH, Hope MJ. Cholesterol mobilization and regression of atheroma in cholesterol-fed rabbits induced by large unilamellar vesicles. Biochim Biophys Acta. 1998; 1368: 306–320.

    Chiesa G, Monteggia E, Marchesi M, Lorenzon P, Laucello M, Lorusso V, Di Mario C, Karvouni E, Newton RS, Bisgaier CL, Franceschini G, Sirtori CR. Recombinant apolipoprotein A-IMilano infusion into rabbit carotid artery rapidly removes lipid from fatty streaks. Circ Res. 2002; 90: 974–980.

    Davies MJ, Richardson PD, Woolf N, Katz DR, Mann J. Risk of thrombosis in human atherosclerotic plaques: role of extracellular lipid, macrophage, and smooth muscle cell content. Br Heart J. 1993; 69: 377–381.

    Naghavi M, Libby P, Falk E, Casscells SW, Litovsky S, Rumberger J, Badimon JJ, Stefanadis C, Moreno P, Pasterkamp G, Fayad Z, Stone PH, Waxman S, Raggi P, Madjid M, Zarrabi A, Burke A, Yuan C, Fitzgerald PJ, Siscovick DS, de Korte CL, Aikawa M, Juhani Airaksinen KE, Assmann G, Becker CR, Chesebro JH, Farb A, Galis ZS, Jackson C, Jang IK, Koenig W, Lodder RA, March K, Demirovic J, Navab M, Priori SG, Rekhter MD, Bahr R, Grundy SM, Mehran R, Colombo A, Boerwinkle E, Ballantyne C, Insull W Jr, Schwartz RS, Vogel R, Serruys PW, Hansson GK, Faxon DP, Kaul S, Drexler H, Greenland P, Muller JE, Virmani R, Ridker PM, Zipes DP, Shah PK, Willerson JT. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I. Circulation. 2003; 108: 1664–1672.

    Contopoulos-Ioannidis DG, Ntzani E, Ioannidis JP. Translation of highly promising basic science research into clinical applications. Am J Med. 2003; 114: 477–484.

    Crowley WF Jr. Translation of basic research into useful treatments: how often does it occur? Am J Med. 2003; 114: 503–505.(Kevin Jon Williams; Ira T)