Cardioprotective functions of HDLs
2013; Elsevier BV; Volume: 55; Issue: 2 Linguagem: Inglês
10.1194/jlr.r039297
ISSN1539-7262
AutoresKerry‐Anne Rye, Philip J. Barter,
Tópico(s)Cholesterol and Lipid Metabolism
ResumoMultiple human population studies have established the concentration of high density lipoprotein (HDL) cholesterol as an independent, inverse predictor of the risk of having a cardiovascular event. Furthermore, HDLs have several well-documented functions with the potential to protect against cardiovascular disease. These include an ability to promote the efflux of cholesterol from macrophages in the artery wall, inhibit the oxidative modification of low density lipoproteins (LDLs), inhibit vascular inflammation, inhibit thrombosis, promote endothelial repair, promote angiogenesis, enhance endothelial function, improve diabetic control, and inhibit hematopoietic stem cell proliferation. There are undoubtedly other beneficial functions of HDLs yet to be identified. The HDL fraction in human plasma is heterogeneous, consisting of several subpopulations of particles of varying size, density, and composition. The functions of the different HDL subpopulations remain largely unknown. Given that therapies that increase the concentration of HDL cholesterol have varying effects on the levels of specific HDL subpopulations, it is of great importance to understand how distribution of different HDL subpopulations contribute to the potentially cardioprotective functions of this lipoprotein fraction. This review summarizes current understanding of the relationship of HDL subpopulations to their cardioprotective properties and highlights the gaps in current knowledge regarding this important aspect of HDL biology. Multiple human population studies have established the concentration of high density lipoprotein (HDL) cholesterol as an independent, inverse predictor of the risk of having a cardiovascular event. Furthermore, HDLs have several well-documented functions with the potential to protect against cardiovascular disease. These include an ability to promote the efflux of cholesterol from macrophages in the artery wall, inhibit the oxidative modification of low density lipoproteins (LDLs), inhibit vascular inflammation, inhibit thrombosis, promote endothelial repair, promote angiogenesis, enhance endothelial function, improve diabetic control, and inhibit hematopoietic stem cell proliferation. There are undoubtedly other beneficial functions of HDLs yet to be identified. The HDL fraction in human plasma is heterogeneous, consisting of several subpopulations of particles of varying size, density, and composition. The functions of the different HDL subpopulations remain largely unknown. Given that therapies that increase the concentration of HDL cholesterol have varying effects on the levels of specific HDL subpopulations, it is of great importance to understand how distribution of different HDL subpopulations contribute to the potentially cardioprotective functions of this lipoprotein fraction. This review summarizes current understanding of the relationship of HDL subpopulations to their cardioprotective properties and highlights the gaps in current knowledge regarding this important aspect of HDL biology. The proposition that high density lipoproteins (HDLs) protect against the development of cardiovascular diseases is based on a number of robust and consistent observations: i) numerous human population studies have shown that the plasma concentrations of both HDL cholesterol and the major HDL apolipoprotein, apoA-I, are independent, inverse predictors of the risk of having a cardiovascular event (1Gordon D.J. Knoke J. Probstfield J.L. Superko R. Tyroler H.A. High-density lipoprotein cholesterol and coronary heart disease in hypercholesterolemic men: the Lipid Research Clinics Coronary Primary Prevention Trial.Circulation. 1986; 74: 1217-1225Crossref PubMed Google Scholar, 2Miller N.E. Thelle D.S. Forde O.H. Mjos O.D. The Tromso heart-study. High-density lipoprotein and coronary heart-disease: a prospective case-control study.Lancet. 1977; 1: 965-968Abstract PubMed Google Scholar, 3Gordon T. Castelli W.P. Hjortland M.C. Kannel W.B. Dawber T.R. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study.Am. J. Med. 1977; 62: 707-714Abstract Full Text PDF PubMed Scopus (3890) Google Scholar, 4Miller M. Seidler A. Kwiterovich P.O. Pearson T.A. Long-term predictors of subsequent cardiovascular events with coronary artery disease and 'desirable' levels of plasma total cholesterol.Circulation. 1992; 86: 1165-1170Crossref PubMed Google Scholar, 5Di Angelantonio E. Sarwar N. Perry P. Kaptoge S. Ray K.K. Thompson A. Wood A.M. Lewington S. Sattar N. Packard C.J. et al.Major lipids, apolipoproteins, and risk of vascular disease.JAMA. 2009; 302: 1993-2000Crossref PubMed Scopus (1651) Google Scholar); moreover, a low concentration of HDL cholesterol remains predictive of increased cardiovascular risk, even when low density lipoprotein (LDL) cholesterol has been reduced to very low levels by treatment with statins (6Barter P. Gotto A.M. LaRosa J.C. Maroni J. Szarek M. Grundy S.M. Kastelein J.J. Bittner V. Fruchart J.C. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events.N. Engl. J. Med. 2007; 357: 1301-1310Crossref PubMed Scopus (1211) Google Scholar); ii) HDLs have several well-documented functions with the potential to protect against cardiovascular disease (7Rye K.A. Bursill C.A. Lambert G. Tabet F. Barter P.J. The metabolism and anti-atherogenic properties of HDL.J. Lipid Res. 2009; 50: S195-S200Abstract Full Text Full Text PDF PubMed Google Scholar, 8Barter P.J. Nicholls S. Rye K.A. Anantharamaiah G.M. Navab M. Fogelman A.M. Antiinflammatory properties of HDL.Circ. Res. 2004; 95: 764-772Crossref PubMed Scopus (950) Google Scholar); iii) interventions that increase the concentration of HDLs inhibit the development and progression of atherosclerosis in several animal models (9Badimon J.J. Badimon L. Fuster V. Regression of atherosclerotic lesions by high density lipoprotein plasma fraction in the cholesterol-fed rabbit.J. Clin. Invest. 1990; 85: 1234-1241Crossref PubMed Google Scholar, 10Rubin E.M. Krauss R.M. Spangler E.A. Verstuyft J.G. Clift S.M. Inhibition of early atherogenesis in transgenic mice by human apolipoprotein AI.Nature. 1991; 353: 265-267Crossref PubMed Scopus (820) Google Scholar, 11Duverger N. Kruth H. Emmanuel F. Caillaud J.M. Viglietta C. Castro G. Tailleux A. Fievet C. Fruchart J.C. Houdebine L.M. et al.Inhibition of atherosclerosis development in cholesterol-fed human apolipoprotein A-I-transgenic rabbits.Circulation. 1996; 94: 713-717Crossref PubMed Google Scholar, 12Nicholls S.J. Cutri B. Worthley S.G. Kee P. Rye K.A. Bao S. Barter P.J. Impact of short-term administration of high-density lipoproteins and atorvastatin on atherosclerosis in rabbits.Arterioscler. Thromb. Vasc. Biol. 2005; 25: 2416-2421Crossref PubMed Scopus (131) Google Scholar); and iv) in "proof-of-concept" studies in humans, intravenous infusions of reconstituted HDLs (rHDLs) consisting of apoA-I complexed with phospholipids promote regression of coronary atheroma as assessed by intravascular ultrasound (13Nissen S.E. Tsunoda T. Tuzcu E.M. Schoenhagen P. Cooper C.J. Yasin M. Eaton G.M. Lauer M.A. Sheldon W.S. Grines C.L. et al.Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial.JAMA. 2003; 290: 2292-2300Crossref PubMed Scopus (1482) Google Scholar, 14Tardif J.C. Gregoire J. L'Allier P.L. Ibrahim R. Lesperance J. Heinonen T.M. Kouz S. Berry C. Basser R. Lavoie M.A. et al.Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial.JAMA. 2007; 297: 1675-1682Crossref PubMed Scopus (573) Google Scholar). However, interventions that increase the concentration of HDL cholesterol in humans have not yet been shown to translate into a reduction in clinical cardiovascular events. Indeed, recent human clinical trials investigating the effects of raising the level of HDL cholesterol by treatment with cholesteryl ester transfer protein (CETP) inhibitors or with niacin failed to demonstrate any clinical cardiovascular benefit (15Barter P.J. Caulfield M. Eriksson M. Grundy S.M. Kastelein J.J. Komajda M. Lopez-Sendon J. Mosca L. Tardif J.C. Waters D.D. et al.Effects of torcetrapib in patients at high risk for coronary events.N. Engl. J. Med. 2007; 357: 2109-2122Crossref PubMed Scopus (2380) Google Scholar, 16Boden W.E. Probstfield J.L. Anderson T. Chaitman B.R. Desvignes-Nickens P. Koprowicz K. McBride R. Teo K. Weintraub W. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy.N. Engl. J. Med. 2011; 365: 2255-2267Crossref PubMed Scopus (1972) Google Scholar, 17Schwartz G.G. Olsson A.G. Abt M. Ballantyne C.M. Barter P.J. Brumm J. Chaitman B.R. Holme I.M. Kallend D. Leiter L.A. et al.Effects of dalcetrapib in patients with a recent acute coronary syndrome.N. Engl. J. Med. 2012; 367: 2089-2099Crossref PubMed Scopus (1353) Google Scholar) (http://www.thrivestudy.org), and in one case, the treatment caused harm (15Barter P.J. Caulfield M. Eriksson M. Grundy S.M. Kastelein J.J. Komajda M. Lopez-Sendon J. Mosca L. Tardif J.C. Waters D.D. et al.Effects of torcetrapib in patients at high risk for coronary events.N. Engl. J. Med. 2007; 357: 2109-2122Crossref PubMed Scopus (2380) Google Scholar). A reasonable assumption that has been made from these studies is that the cholesterol content of HDLs is not the factor that protects. Thus, if HDLs do have direct cardioprotective properties, it follows from the human population studies that, while the concentration of HDL cholesterol is generally an excellent marker of the HDL functions that do protect, it does not invariably reflect their cardioprotective functions. This is consistent with the finding in a recent Mendelian randomization study that some genetic mechanisms that raise the concentration of HDL cholesterol appear not to lower the risk of myocardial infarction (18Voight B.F. Peloso G.M. Orho-Melander M. Frikke-Schmidt R. Barbalic M. Jensen M.K. Hindy G. Holm H. Ding E.L. Johnson T. et al.Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study.Lancet. 2012; 380: 572-580Abstract Full Text Full Text PDF PubMed Scopus (1370) Google Scholar). The authors of this analysis concluded that, while this result challenges the concept that raising the concentration of HDL cholesterol will translate into a reduction in risk of myocardial infarction, it did not address the possibility that an enhancement of HDL function would be protective. For example, in some clinical circumstances, a high concentration of HDL cholesterol is not accompanied by a decrease in cardiovascular risk (19van der Steeg W.A. Holme I. Boekholdt S.M. Larsen M.L. Lindahl C. Stroes E.S. Tikkanen M.J. Wareham N.J. Faergeman O. Olsson A.G. et al.High-density lipoprotein cholesterol, high-density lipoprotein particle size, and apolipoprotein A-I: significance for cardiovascular risk: the IDEAL and EPIC-Norfolk studies.J. Am. Coll. Cardiol. 2008; 51: 634-642Crossref PubMed Scopus (255) Google Scholar). This may reflect the fact that an intervention that raises the level of HDL cholesterol is not necessarily accompanied by an increase in the functionality of the HDL fraction. This leads to an obvious question, Given the robust evidence from animal and human population studies that HDLs are antiatherogenic, why have recent clinical trials using agents that increase the level of HDL cholesterol failed to demonstrate a reduction in clinical cardiovascular events? There are several potential explanations for this. It is possible that the inverse relationship between the concentration of HDL cholesterol and cardiovascular risk observed in human population studies is an epiphenomenon rather than a direct cardioprotective effect. However, this is not supported by many animal studies showing that atherosclerosis is inhibited by interventions that increase the level of HDL cholesterol (9Badimon J.J. Badimon L. Fuster V. Regression of atherosclerotic lesions by high density lipoprotein plasma fraction in the cholesterol-fed rabbit.J. Clin. Invest. 1990; 85: 1234-1241Crossref PubMed Google Scholar, 10Rubin E.M. Krauss R.M. Spangler E.A. Verstuyft J.G. Clift S.M. Inhibition of early atherogenesis in transgenic mice by human apolipoprotein AI.Nature. 1991; 353: 265-267Crossref PubMed Scopus (820) Google Scholar, 11Duverger N. Kruth H. Emmanuel F. Caillaud J.M. Viglietta C. Castro G. Tailleux A. Fievet C. Fruchart J.C. Houdebine L.M. et al.Inhibition of atherosclerosis development in cholesterol-fed human apolipoprotein A-I-transgenic rabbits.Circulation. 1996; 94: 713-717Crossref PubMed Google Scholar, 12Nicholls S.J. Cutri B. Worthley S.G. Kee P. Rye K.A. Bao S. Barter P.J. Impact of short-term administration of high-density lipoproteins and atorvastatin on atherosclerosis in rabbits.Arterioscler. Thromb. Vasc. Biol. 2005; 25: 2416-2421Crossref PubMed Scopus (131) Google Scholar). It is also possible, but unlikely, that the ability of HDLs to inhibit the development of atherosclerosis in animals and to promote regression of atherosclerosis in humans does not necessarily translate into an ability of HDLs to reduce clinical cardiovascular events in humans. There is also evidence that some agents that increase HDL cholesterol levels have adverse off-target effects that may negate the benefit conferred by the HDL elevation. This may well have been the case with the CETP inhibitor torcetrapib (15Barter P.J. Caulfield M. Eriksson M. Grundy S.M. Kastelein J.J. Komajda M. Lopez-Sendon J. Mosca L. Tardif J.C. Waters D.D. et al.Effects of torcetrapib in patients at high risk for coronary events.N. Engl. J. Med. 2007; 357: 2109-2122Crossref PubMed Scopus (2380) Google Scholar). It is also possible that a niacin-induced insulin resistance (20Poynten A.M. Gan S.K. Kriketos A.D. O'Sullivan A. Kelly J.J. Ellis B.A. Chisholm D.J. Campbell L.V. Nicotinic acid-induced insulin resistance is related to increased circulating fatty acids and fat oxidation but not muscle lipid content.Metabolism. 2003; 52: 699-704Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar) may partially negate the effects of this agent on HDLs. Furthermore, it has been suggested that increasing HDL cholesterol levels may be ineffective in statin-treated patients in whom the concentration of LDL cholesterol is very low (21Ridker P.M. Genest J. Boekholdt S.M. Libby P. Gotto A.M. Nordestgaard B.G. Mora S. MacFadyen J.G. Glynn R.J. Kastelein J.J. HDL cholesterol and residual risk of first cardiovascular events after treatment with potent statin therapy: an analysis from the JUPITER trial.Lancet. 2010; 376: 333-339Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar), although there is little evidence to support this. It is also possible that in some studies the ability of HDL cholesterol-raising agents to reduce cardiovascular events was tested in people in whom HDL function was compromised. This may well have been the case in the population of acute coronary syndrome patients studied in the Dal-OUTCOME trial, in which even in the placebo group, there was no evidence of a relationship between HDL cholesterol levels and cardiovascular events (17Schwartz G.G. Olsson A.G. Abt M. Ballantyne C.M. Barter P.J. Brumm J. Chaitman B.R. Holme I.M. Kallend D. Leiter L.A. et al.Effects of dalcetrapib in patients with a recent acute coronary syndrome.N. Engl. J. Med. 2012; 367: 2089-2099Crossref PubMed Scopus (1353) Google Scholar). This observation raised the possibility, as has been reported in ex vivo studies (22Besler C. Heinrich K. Rohrer L. Doerries C. Riwanto M. Shih D.M. Chroni A. Yonekawa K. Stein S. Schaefer N. et al.Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease.J. Clin. Invest. 2011; 121: 2693-2708Crossref PubMed Scopus (400) Google Scholar), that the cardioprotective properties of the HDLs are compromised after an acute coronary syndrome. If this is true, it follows that increasing endogenous HDL levels in these individuals may not lead to a reduction in cardiovascular events. These observations raise several questions and highlight major gaps in current knowledge about the relationship between HDL and cardiovascular disease. For example, it is not known which HDL functions are clinically important, nor is it known whether some functions are more cardioprotective than others. Moreover, we know little about the functionality of individual HDL subpopulations. Nor do we know whether therapeutic interventions that increase the concentration of HDL cholesterol are necessarily accompanied by an enhancement of HDL function. This review is concerned with what is currently known about the potentially cardioprotective functions of HDL, and it highlights the gaps in current knowledge regarding this important aspect of HDL biology. In the interest of keeping the size of the review manageable, it has not been possible to cite all of the references that would otherwise be worthy of inclusion. Several well-documented functions of HDLs and apoA-I have the potential to protect against cardiovascular disease. The most extensively studied of these relates to the ability of HDLs to promote efflux of cholesterol from macrophages in the artery wall (23Duffy D. Rader D.J. Emerging therapies targeting high-density lipoprotein metabolism and reverse cholesterol transport.Circulation. 2006; 113: 1140-1150Crossref PubMed Scopus (92) Google Scholar). HDLs also inhibit vascular inflammation (8Barter P.J. Nicholls S. Rye K.A. Anantharamaiah G.M. Navab M. Fogelman A.M. Antiinflammatory properties of HDL.Circ. Res. 2004; 95: 764-772Crossref PubMed Scopus (950) Google Scholar, 24Cockerill G.W. Rye K.A. Gamble J.R. Vadas M.A. Barter P.J. High-density lipoproteins inhibit cytokine-induced expression of endothelial cell adhesion molecules.Arterioscler. Thromb. Vasc. Biol. 1995; 15: 1987-1994Crossref PubMed Google Scholar) and has antioxidant (8Barter P.J. Nicholls S. Rye K.A. Anantharamaiah G.M. Navab M. Fogelman A.M. Antiinflammatory properties of HDL.Circ. Res. 2004; 95: 764-772Crossref PubMed Scopus (950) Google Scholar) and antithrombotic (25Mineo C. Deguchi H. Griffin J.H. Shaul P.W. Endothelial and antithrombotic actions of HDL.Circ. Res. 2006; 98: 1352-1364Crossref PubMed Scopus (453) Google Scholar) properties. They enhance endothelial function (26Bisoendial R.J. Hovingh G.K. Levels J.H. Lerch P.G. Andresen I. Hayden M.R. Kastelein J.J. Stroes E.S. Restoration of endothelial function by increasing high-density lipoprotein in subjects with isolated low high-density lipoprotein.Circulation. 2003; 107: 2944-2948Crossref PubMed Scopus (270) Google Scholar), promote endothelial repair (27Seetharam D. Mineo C. Gormley A.K. Gibson L.L. Vongpatanasin W. Chambliss K.L. Hahner L.D. Cummings M.L. Kitchens R.L. Marcel Y.L. et al.High-density lipoprotein promotes endothelial cell migration and reendothelialization via scavenger receptor-B type I.Circ. Res. 2006; 98: 63-72Crossref PubMed Scopus (218) Google Scholar, 28Tso C. Martinic G. Fan W.H. Rogers C. Rye K.A. Barter P.J. High-density lipoproteins enhance progenitor-mediated endothelium repair in mice.Arterioscler. Thromb. Vasc. Biol. 2006; 26: 1144-1149Crossref PubMed Scopus (145) Google Scholar), increase angiogenesis (29Sumi M. Sata M. Miura S. Rye K.A. Toya N. Kanaoka Y. Yanaga K. Ohki T. Saku K. Nagai R. Reconstituted high-density lipoprotein stimulates differentiation of endothelial progenitor cells and enhances ischemia-induced angiogenesis.Arterioscler. Thromb. Vasc. Biol. 2007; 27: 813-818Crossref PubMed Scopus (106) Google Scholar), suppress the production and mobilization of monocytes and neutrophils from bone marrow (30Yvan-Charvet L. Pagler T. Gautier E.L. Avagyan S. Siry R.L. Han S. Welch C.L. Wang N. Randolph G.J. Snoeck H.W. et al.ATP-binding cassette transporters and HDL suppress hematopoietic stem cell proliferation.Science. 2010; 328: 1689-1693Crossref PubMed Scopus (434) Google Scholar), and have recently been reported to have antidiabetic properties (31Drew B.G. Duffy S.J. Formosa M.F. Natoli A.K. Henstridge D.C. Penfold S.A. Thomas W.G. Mukhamedova N. de Courten B. Forbes J.M. et al.High-density lipoprotein modulates glucose metabolism in patients with type 2 diabetes mellitus.Circulation. 2009; 119: 2103-2111Crossref PubMed Scopus (259) Google Scholar, 32Drew B.G. Rye K.A. Duffy S.J. Barter P. Kingwell B.A. The emerging role of HDL in glucose metabolism.Nat. Rev. Endocrinol. 2012; 8: 237-245Crossref PubMed Scopus (133) Google Scholar). Which of these functions of HDLs are clinically important is not known. Nor is it known which HDL component(s) or subpopulations are responsible for these potentially cardioprotective properties. This lack of insight is largely due to the fact that HDLs consist of multiple subpopulations of particles that are continually being interconverted from one to another by a range of plasma factors (33Rye K.A. Barter P.J. Formation and metabolism of prebeta-migrating, lipid-poor apolipoprotein A-I.Arterioscler. Thromb. Vasc. Biol. 2004; 24: 421-428Crossref PubMed Scopus (252) Google Scholar), as well as by the fact that it is currently not feasible to isolate specific HDL subpopulations in amounts that are sufficient to investigate their functionality in a systematic manner. The HDLs in human plasma are heterogeneous in terms of particle density, size, shape, surface charge, and composition (34Rye K.A. Clay M.A. Barter P.J. Remodelling of high density lipoproteins by plasma factors.Atherosclerosis. 1999; 145: 227-238Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar). When isolated on the basis of density, human HDLs can be resolved into two major subfractions: HDL2 which comprises large, less dense particles and HDL3, which consists of smaller, denser particles. Separation of the total HDL fraction on the basis of particle size by nondenaturing polyacrylamide gradient gel electrophoresis has identified at least five distinct HDL subpopulations (35Blanche P.J. Gong E.L. Forte T.M. Nichols A.V. Characterization of human high-density lipoproteins by gradient gel electrophoresis.Biochim. Biophys. Acta. 1981; 665: 408-419Crossref PubMed Scopus (433) Google Scholar). HDLs also vary in surface charge and can be resolved on this basis by agarose gel electrophoresis into several subpopulations. According to this approach, α-migrating particles equate with the spherical HDL particles that predominate in human plasma, while pre-β-migrating particles comprise a single molecule of lipid-poor apoA-I, a single molecule of apoA-I complexed with a small number of phospholipid molecules, or discoidal particles that contain two or three molecules of apoA-I complexed with multiple phospholipid molecules plus a small amount of unesterified cholesterol (36Castro G.R. Fielding C.J. Early incorporation of cell-derived cholesterol into pre-beta-migrating high-density lipoprotein.Biochemistry. 1988; 27: 25-29Crossref PubMed Google Scholar). Discrete HDL subpopulations have also been identified on the basis of their apolipoprotein composition: those that contain apoA-I but are deficient in apoA-II, the second most abundant HDL apolipoprotein (A-I HDLs), and those that contain both apoA-I and apoA-II (A-I/A-II HDLs) (37Cheung M.C. Albers J.J. Characterization of lipoprotein particles isolated by immunoaffinity chromatography. Particles containing A-I and A-II and particles containing A-I but no A-II.J. Biol. Chem. 1984; 259: 12201-12209Abstract Full Text PDF PubMed Google Scholar). A minor subpopulation of apoE-containing, γ-migrating HDL particles has also been reported (38Huang Y. von Eckardstein A. Wu S. Maeda N. Assmann G. A plasma lipoprotein containing only apolipoprotein E and with gamma mobility on electrophoresis releases cholesterol from cells.Proc. Natl. Acad. Sci. USA. 1994; 91: 1834-1838Crossref PubMed Google Scholar). It has been suggested that A-I HDLs may be superior to A-I/A-II HDLs in their ability to protect against atherosclerosis (39Amouyel P. Isorez D. Bard J.M. Goldman M. Lebel P. Zylberberg G. Fruchart J.C. Parental history of early myocardial infarction is associated with decreased levels of lipoparticle AI in adolescents.Arterioscler. Thromb. 1993; 13: 1640-1644Crossref PubMed Google Scholar), although evidence for this is associative and requires confirmation in large prospective population studies. It has also been suggested that particles in the HDL2 subfraction may be more cardioprotective than those in the HDL3 subfraction (40Miller N.E. Associations of high-density lipoprotein subclasses and apolipoproteins with ischemic heart disease and coronary atherosclerosis.Am. Heart J. 1987; 113: 589-597Crossref PubMed Scopus (393) Google Scholar), although other studies have concluded that a very high concentration of large, cholesterol-rich HDL2 particles, when not accompanied by a correspondingly high level of apoA-I-containing HDL, may be associated with increased rather than decreased cardiovascular risk (19van der Steeg W.A. Holme I. Boekholdt S.M. Larsen M.L. Lindahl C. Stroes E.S. Tikkanen M.J. Wareham N.J. Faergeman O. Olsson A.G. et al.High-density lipoprotein cholesterol, high-density lipoprotein particle size, and apolipoprotein A-I: significance for cardiovascular risk: the IDEAL and EPIC-Norfolk studies.J. Am. Coll. Cardiol. 2008; 51: 634-642Crossref PubMed Scopus (255) Google Scholar). Thus, the evidence linking cardioprotection to specific HDL subpopulations in humans is both limited and conflicting. There is compelling evidence from human studies that interventions that raise the level of HDL cholesterol have varying effects on specific HDL subpopulations. For example, statins (41Johansson J. Molgaard J. Olsson A.G. Plasma high density lipoprotein particle size alteration by simvastatin treatment in patients with hypercholesterolaemia.Atherosclerosis. 1991; 91: 175-184Abstract Full Text PDF PubMed Scopus (0) Google Scholar, 42Neuman M.P. Neuman H.R. Neuman J. Significant increase of high-density lipoprotein2-cholesterol under prolonged simvastatin treatment.Atherosclerosis. 1991; 91: S11-S19Abstract Full Text PDF PubMed Google Scholar), niacin (43Kuvin J.T. Dave D.M. Sliney K.A. Mooney P. Patel A.R. Kimmelstiel C.D. Karas R.H. Effects of extended-release niacin on lipoprotein particle size, distribution, and inflammatory markers in patients with coronary artery disease.Am. J. Cardiol. 2006; 98: 743-745Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar), and CETP inhibitors (44Brousseau M.E. Schaefer E.J. Wolfe M.L. Bloedon L.T. Digenio A.G. Clark R.W. Mancuso J.P. Rader D.J. Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol.N. Engl. J. Med. 2004; 350: 1505-1515Crossref PubMed Scopus (682) Google Scholar) tend to increase the concentration of large, apoA-I-containing HDLs. Fibrates, on the other hand, tend to increase levels of smaller HDL particles that contain both apoA-I and apoA-II (45Bard J.M. Parra H.J. Camare R. Luc G. Ziegler O. Dachet C. Bruckert E. Douste-Blazy P. Drouin P. Jacotot B. et al.A multicenter comparison of the effects of simvastatin and fenofibrate therapy in severe primary hypercholesterolemia, with particular emphasis on lipoproteins defined by their apolipoprotein composition.Metabolism. 1992; 41: 498-503Abstract Full Text PDF PubMed Scopus (0) Google Scholar). The clinical implications of these differences are not known. There is also evidence from animal studies that different approaches to raising the concentration of HDL cholesterol may vary markedly in terms of their ability to inhibit atherosclerosis. For example, there is robust and consistent evidence that overexpression of apoA-I in mice (10Rubin E.M. Krauss R.M. Spangler E.A. Verstuyft J.G. Clift S.M. Inhibition of early atherogenesis in transgenic mice by human apolipoprotein AI.Nature. 1991; 353: 265-267Crossref PubMed Scopus (820) Google Scholar, 46Plump A.S. Scott C.J. Breslow J.L. Human apolipoprotein A-I gene expression increases high density lipoprotein and suppresses atherosclerosis in the apolipoprotein E-deficient mouse.Proc. Natl. Acad. Sci. USA. 1994; 91: 9607-9611Crossref PubMed Google Scholar) and rabbits (11Duverger N. Kruth H. Emmanuel F. Caillaud J.M. Viglietta C. Castro G. Tailleux A. Fievet C. Fruchart J.C. Houdebine L.M. et al.Inhibition of atherosclerosis development in cholesterol-fed human apolipoprotein A-I-transgenic rabbits.Circulation. 1996; 94: 713-717Crossref PubMed Google Scholar), as well as intravenous infusions of native HDLs or rHDLs into these animals (9Badimon J.J. Badimon L. Fuster V. Regression of atherosclerotic lesions by high density lipoprotein plasma fraction in the cholesterol-fed rabbit.J. Clin. Invest. 1990; 85: 1234-1241Crossref PubMed Google Scholar, 47Chiesa G. Monteggia E. Marchesi M. Lorenzon P. Laucello M. Lorusso V. Di Mario C. Karvouni E. Newton R.S. Bisgaier C.L. et al.Recombinant apolipoprotein A-I(Milano) infusion into rabbit carotid artery rapidly removes lipid from fatty streaks.Circ. Res. 2002; 90: 974-980Crossref PubMed Scopus (168) Google Scholar), inhibits the development of atherosclerosis. There is also consistent evidence that increasing endogenous HDL cholesterol levels by inhibiting CETP (48Okamoto H. Yonemori F. Wakitani K. Minowa T. Maeda K. Shinkai H. A cholesteryl ester transfer protein inhibitor attenuates atherosclerosis in rabbits.Nature. 2000; 406: 203-207Crossref PubMed Scopus (491) Google Scholar, 49Morehouse L.A. Sugarman E.D. Bourassa P.A. Sand T.M. Zimetti F. Gao F. Rothblat G.H. Milici A.J. Inhibition of CETP activity by torcetrapib reduces susceptibility to diet-induced atherosclerosis in New Zealand White rabbits.J. Lipid Res. 2007; 48: 1263-1272Abstract Full Text F
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