Levels of high-density lipoprotein (HDL) cholesterol are generally inversely associated with the risk for the development of atherosclerosis. The mechanism by which HDL imparts protection from the initiation and progression of occlusive vascular disease is complex and multifactorial. The major anti-atherosclerotic effect of HDL is felt to be reverse cholesterol transport. HDL has been demonstrated to scavenge cholesterol from the peripheral vasculature with transport to the liver, where is it excreted in the biliary system. However, HDL exhibits multiple other physiologic effects that may play a role in the reduced risk for atherosclerosis. HDL has been demonstrated to exhibit beneficial effects on platelet function, endothelial function, coagulation parameters, inflammation, and interactions with triglyceride-rich lipoproteins. Increasing amounts of clinical and experimental data have shown that HDL cholesterol has significant antioxidant effect that may significantly contribute to protection from atherosclerosis.
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Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Barter P, et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med. 2007;357(13):1301–10.
•• Brufau G, Groen AK, Kuipers F. Reverse cholesterol transport revisited: contribution of biliary versus intestinal cholesterol excretion. Arterioscler Thromb Vasc Biol. 2011;31(8):1726–33. This is an excellent review of alternatives mechanisms in the removal of cholesterol stores from vascular depots and subsequent excretion into the gastrointestinal tract.
Assmann G, Gotto Jr AM. HDL cholesterol and protective factors in atherosclerosis. Circulation. 2004;109(23 Suppl 1):III8–III14.
Florentin M, et al. Multiple actions of high-density lipoprotein. Curr Opin Cardiol. 2008;23(4):370–8.
• Williams PT, Feldman DE. Prospective study of coronary heart disease vs. HDL2, HDL3, and other lipoproteins in Gofman's Livermore Cohort. Atherosclerosis. 2011;214(1):196–202. This is an epidemiologic study that provides a mechanism and rationale for the correlation of cardiovascular risk with various HDL subfractions.
Kontush A, Chapman MJ. Antiatherogenic function of HDL particle subpopulations: focus on antioxidative activities. Curr Opin Lipidol. 2010;21(4):312–8.
Tall AR. Functions of cholesterol ester transfer protein and relationship to coronary artery disease risk. J Clin Lipidol. 2010;4(5):389–93.
•• Sanz J, Fuster V. The year in atherothrombosis. J Am Coll Cardiol. 2011;58(8):779–91. This article contains comprehensive reviews of major advances over the past 12 months, including a review of multiple studies of HDL including epidemiologic correlations and studies utilizing nicotinic acid and fibric acid derivatives. Additionally, references are provided for the role of cholesterol ester transfer protein and cardiovascular outcomes. The role of HDL mimetics is also discussed.
van Hinsbergh, V. W. Endothelium-role in regulation of coagulation and inflammation. Semin Immunopathol. 2011.
Turner EC, et al. Interaction of the human prostacyclin receptor with the PDZ adapter protein PDZK1: role in endothelial cell migration and angiogenesis. Mol Biol Cell. 2011;22(15):2664–79.
Appel SJ, Harrell JS, Davenport ML. Central obesity, the metabolic syndrome, and plasminogen activator inhibitor-1 in young adults. J Am Acad Nurse Pract. 2005;17(12):535–41.
Superko RH. Lipoprotein subclasses and atherosclerosis. Front Biosci. 2001;6:D355–65.
Donati MB. The "common soil hypothesis": evidence from population studies? Thromb Res. 2010;125 Suppl 2:S92–5.
Madamanchi NR, Hakim ZS, Runge MS. Oxidative stress in atherogenesis and arterial thrombosis: the disconnect between cellular studies and clinical outcomes. J Thromb Haemost. 2005;3(2):254–67.
Bonomini F, et al. Atherosclerosis and oxidative stress. Histol Histopathol. 2008;23(3):381–90.
Nicholls SJ, et al. Reconstituted high-density lipoproteins inhibit the acute pro-oxidant and proinflammatory vascular changes induced by a periarterial collar in normocholesterolemic rabbits. Circulation. 2005;111(12):1543–50.
Steinbrecher UP, Zhang HF, Lougheed M. Role of oxidatively modified LDL in atherosclerosis. Free Radic Biol Med. 1990;9(2):155–68.
Stocker R, Keaney Jr JF. Role of oxidative modifications in atherosclerosis. Physiol Rev. 2004;84(4):1381–478.
Napoli C, de Nigris F, Palinski W. Multiple role of reactive oxygen species in the arterial wall. J Cell Biochem. 2001;82(4):674–82.
Navab M, et al. The oxidation hypothesis of atherogenesis: the role of oxidized phospholipids and HDL. J Lipid Res. 2004;45(6):993–1007.
Negre-Salvayre A, et al. Antioxidant and cytoprotective properties of high-density lipoproteins in vascular cells. Free Radic Biol Med. 2006;41(7):1031–40.
Kunitake ST, et al. Binding of transition metals by apolipoprotein A-I-containing plasma lipoproteins: inhibition of oxidation of low density lipoproteins. Proc Natl Acad Sci U S A. 1992;89(15):6993–7.
Klimov AN, et al. On the ability of high density lipoproteins to remove phospholipid peroxidation products from erythrocyte membranes. Biochemistry (Mosc). 2001;66(3):300–4.
Ribas V, et al. Human apolipoprotein A-II enrichment displaces paraoxonase from HDL and impairs its antioxidant properties: a new mechanism linking HDL protein composition and antiatherogenic potential. Circ Res. 2004;95(8):789–97.
Garner B, et al. Oxidation of high density lipoproteins. II. Evidence for direct reduction of lipid hydroperoxides by methionine residues of apolipoproteins AI and AII. J Biol Chem. 1998;273(11):6088–95.
Chiesa G, Sirtori CR. Apolipoprotein A-I(Milano): current perspectives. Curr Opin Lipidol. 2003;14(2):159–63.
Nissen SE, et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA. 2003;290(17):2292–300.
•• Degoma EM, Rader DJ. Novel HDL-directed pharmacotherapeutic strategies. Nat Rev Cardiol. 2011;8(5):266–77. This is an excellent and comprehensive review of the role of HDL-directed therapies in the prevention of cardiovascular disease. Multiple approaches such as direct or indirect mechanisms to augment Apo A1 levels, utilization of nicotinic acid receptor agonists, endothelial lipase inhibitors, and mimicking of Apo A1 functionality are reviewed in detail. Mechanisms to enhance reverse cholesterol transport are also presented.
Mackness MI, et al. Serum paraoxonase activity in familial hypercholesterolaemia and insulin-dependent diabetes mellitus. Atherosclerosis. 1991;86(2–3):193–9.
Mackness B, et al. Serum paraoxonase activity in patients with type 1 diabetes compared to healthy controls. Eur J Clin Invest. 2002;32(4):259–64.
Precourt LP, et al. The three-gene paraoxonase family: physiologic roles, actions and regulation. Atherosclerosis. 2011;214(1):20–36.
Navab M, et al. HDL and the inflammatory response induced by LDL-derived oxidized phospholipids. Arterioscler Thromb Vasc Biol. 2001;21(4):481–8.
Yost CC, Weyrich AS, Zimmerman GA. The platelet activating factor (PAF) signaling cascade in systemic inflammatory responses. Biochimie. 2010;92(6):692–7.
Penna C, Bassino E, Alloatti G. Platelet activating factor: the good and the bad in the ischemic/reperfused heart. Exp Biol Med (Maywood). 2011;236(4):390–401.
Tselepis AD, John M. Chapman, Inflammation, bioactive lipids and atherosclerosis: potential roles of a lipoprotein-associated phospholipase A2, platelet activating factor-acetylhydrolase. Atheroscler Suppl. 2002;3(4):57–68.
Costa LG, et al. Modulation of paraoxonase (PON1) activity. Biochem Pharmacol. 2005;69(4):541–50.
Salvayre R, et al. Oxidized low-density lipoprotein-induced apoptosis. Biochim Biophys Acta. 2002;1585(2–3):213–21.
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Bandeali, S., Farmer, J. High-Density Lipoprotein and Atherosclerosis: The Role of Antioxidant Activity. Curr Atheroscler Rep 14, 101–107 (2012). https://doi.org/10.1007/s11883-012-0235-2