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Semin Vasc Med 2004; 4(2): 187-195
DOI: 10.1055/s-2004-835377
DOI: 10.1055/s-2004-835377
The Emerging Role of Lipoproteins in Atherogenesis: Beyond LDL Cholesterol
Further Information
Publication History
Publication Date:
11 October 2004 (online)
Low-density lipoprotein cholesterol has a well-established role in atherogenesis and the development of coronary heart disease. However, despite effective lowering of low-density lipoprotein cholesterol, many patients continue to have cardiovascular events. It has subsequently emerged that several additional dyslipidemic states promote atherogenesis. In particular, the atherogenic lipoprotein phenotype comprising an elevation of triglycerides and triglyceride-rich lipoproteins; decreased concentrations of high-density lipoprotein cholesterol; and increased small, dense low-density lipoprotein cholesterol, in addition to impaired postprandial lipemia, have been demonstrated to have profound effects on the arterial wall. As such, these factors have become important targets in the development of effective strategies to prevent atherosclerotic cardiovascular disease.
KEYWORDS
Atherosclerosis - endothelial function - HDL - inflammation - triglycerides
REFERENCES
- 1 Superko H R. Beyond LDL cholesterol reduction. Circulation. 1996; 94 2351-2354
- 2 Cooke J P, Tsao P S. Is NO an endogenous antiatherogenic molecule?. Arterioscler Thromb. 1994; 14 653-655
- 3 Zeiher A M, Drexler H, Saurbier B et al.. Endothelium-mediated coronary blood flow modulation in humans. Effects of age, atherosclerosis, hypercholesterolemia, and hypertension. J Clin Invest. 1993; 92 652-662
- 4 Celermajer D S, Sorensen K E, Bull C et al.. Endothelium-dependent dilation in the systemic arteries of asymptomatic subjects relates to coronary risk factors and their interaction. J Am Coll Cardiol. 1994; 24 1468-1474
- 5 Halcox J P, Schenke W H, Zalos G et al.. Prognostic value of coronary vascular endothelial dysfunction. Circulation. 2002; 106 653-658
- 6 Libby P. Inflammation in atherosclerosis. Nature. 2002; 420 868-874
- 7 Boyle J J. Association of coronary plaque rupture and atherosclerotic inflammation. J Pathol. 1997; 181 93-99
- 8 Ridker P M, Cushman M, Stampfer M J et al.. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997; 336 973-979
- 9 Lam J Y, Latour J G, Lesperance J et al.. Platelet aggregation, coronary artery disease progression and future coronary events. Am J Cardiol. 1994; 73 333-338
- 10 Hamsten A. Hemostatic function and coronary artery disease. N Engl J Med. 1995; 332 677-678
- 11 Yudkin J S, Kumari M, Humphries S E et al.. Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link?. Atherosclerosis. 2000; 148 209-214
- 12 Yudkin J S, Stehouwer C D, Emeis J J et al.. C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue?. Arterioscler Thromb Vasc Biol. 1999; 19 972-978
- 13 Fichtlscherer S, Rosenberger G, Walter D H et al.. Elevated C-reactive protein levels and impaired endothelial vasoreactivity in patients with coronary artery disease. Circulation. 2000; 102 1000-1006
- 14 Hingorani A D, Cross J, Kharbanda R K et al.. Acute systemic inflammation impairs endothelium-dependent dilatation in humans. Circulation. 2000; 102 994-999
- 15 Hokanson J E. Hypertriglyceridemia and risk of coronary heart disease. Curr Cardiol Rep. 2002; 4 488-493
- 16 Vogel R A, Corretti M C, Plotnick G D. Effect of a single high-fat meal on endothelial function in healthy subjects. Am J Cardiol. 1997; 79 350-354
- 17 Steinberg H O, Tarshoby M, Monestel R et al.. Elevated circulating free fatty acid levels impair endothelium- dependent vasodilation. J Clin Invest. 1997; 100 1230-1239
- 18 Lundman P, Eriksson M, Schenck-Gustafsson K et al.. Transient triglyceridemia decreases vascular reactivity in young, healthy men without risk factors for coronary heart disease. Circulation. 1997; 96 3266-3268
- 19 Chowienczyk P J, Watts G F, Wierzbicki A S et al.. Preserved endothelial function in patients with severe hypertriglyceridemia and low functional lipoprotein lipase activity. J Am Coll Cardiol. 1997; 29 964-968
- 20 Lewis T V, Dart A M, Chin-Dusting J P. Endothelium-dependent relaxation by acetylcholine is impaired in hypertriglyceridemic humans with normal levels of plasma LDL cholesterol. J Am Coll Cardiol. 1999; 33 805-812
- 21 de Man F H, Weverling-Rijnsburger A W, van der Laarse A et al.. Not acute but chronic hypertriglyceridemia is associated with impaired endothelium-dependent vasodilation: reversal after lipid-lowering therapy by atorvastatin. Arterioscler Thromb Vasc Biol. 2000; 20 744-750
- 22 Lupattelli G, Lombardini R, Schillaci G et al.. Flow-mediated vasoactivity and circulating adhesion molecules in hypertriglyceridemia: association with small, dense LDL cholesterol particles. Am Heart J. 2000; 140 521-526
- 23 Lundman P, Eriksson M J, Stuhlinger M et al.. Mild-to-moderate hypertriglyceridemia in young men is associated with endothelial dysfunction and increased plasma concentrations of asymmetric dimethylarginine. J Am Coll Cardiol. 2001; 38 111-116
- 24 Schnell G B, Robertson A, Houston D et al.. Impaired brachial artery endothelial function is not predicted by elevated triglycerides. J Am Coll Cardiol. 1999; 33 2038-2043
- 25 Kugiyama K, Doi H, Motoyama T et al.. Association of remnant lipoprotein levels with impairment of endothelium-dependent vasomotor function in human coronary arteries. Circulation. 1998; 97 2519-2526
- 26 Inoue T, Saniabadi A R, Matsunaga R et al.. Impaired endothelium-dependent acetylcholine-induced coronary artery relaxation in patients with high serum remnant lipoprotein particles. Atherosclerosis. 1998; 139 363-367
- 27 Naderali E K, Williams G. Effects of short-term feeding of a highly palatable diet on vascular reactivity in rats. Eur J Clin Invest. 2001; 31 1024-1028
- 28 Lundman P, Tornvall P, Nilsson L et al.. A triglyceride-rich fat emulsion and free fatty acids but not very low density lipoproteins impair endothelium-dependent vasorelaxation. Atherosclerosis. 2001; 159 35-41
- 29 Doi H, Kugiyama K, Ohgushi M et al.. Remnants of chylomicron and very low density lipoprotein impair endothelium-dependent vasorelaxation. Atherosclerosis. 1998; 137 341-349
- 30 Grieve D J, Avella M A, Botham K M et al.. Effects of chylomicrons and chylomicron remnants on endothelium-dependent relaxation of rat aorta. Eur J Pharmacol. 1998; 348 181-190
- 31 Goulter A B, Avella M A, Elliott J et al.. Chylomicron-remnant-like particles inhibit receptor-mediated endothelium-dependent vasorelaxation in pig coronary arteries. Clin Sci (Lond). 2002; 103 451-460
- 32 Lundman P, Eriksson M J, Silveira A et al.. Relation of hypertriglyceridemia to plasma concentrations of biochemical markers of inflammation and endothelial activation (C-reactive protein, interleukin-6, soluble adhesion molecules, von Willebrand factor, and endothelin-1). Am J Cardiol. 2003; 91 1128-1131
- 33 Ridker P M, Buring J E, Cook N R et al.. C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14 719 initially healthy American women. Circulation. 2003; 107 391-397
- 34 Abe Y, El-Masri B, Kimball K T et al.. Soluble cell adhesion molecules in hypertriglyceridemia and potential significance on monocyte adhesion. Arterioscler Thromb Vasc Biol. 1998; 18 723-731
- 35 de Gruijter M, Hoogerbrugge N, van Rijn M A et al.. Patients with combined hypercholesterolemia-hypertriglyceridemia show an increased monocyte-endothelial cell adhesion in vitro: triglyceride level as a major determinant. Metabolism. 1991; 40 1119-1121
- 36 Jongkind J F, Verkerk A, Hoogerbrugge N. Monocytes from patients with combined hypercholesterolemia-hypertriglyceridemia and isolated hypercholesterolemia show an increased adhesion to endothelial cells in vitro: II. Influence of intrinsic and extrinsic factors on monocyte binding. Metabolism. 1995; 44 374-378
- 37 Saxena U, Kulkarni N M, Ferguson E et al.. Lipoprotein lipase-mediated lipolysis of very low density lipoproteins increases monocyte adhesion to aortic endothelial cells. Biochem Biophys Res Commun. 1992; 189 1653-1658
- 38 Moers A, Fenselau S, Schrezenmeir J. Chylomicrons induce E-selectin and VCAM-1 expression in endothelial cells. Exp Clin Endocrinol Diabetes. 1997; 105 35-37
- 39 Gronholdt M L, Nordestgaard B G, Nielsen T G et al.. Echolucent carotid artery plaques are associated with elevated levels of fasting and postprandial triglyceride-rich lipoproteins. Stroke. 1996; 27 2166-2172
- 40 Felton C V, Crook D, Davies M J et al.. Relation of plaque lipid composition and morphology to the stability of human aortic plaques. Arterioscler Thromb Vasc Biol. 1997; 17 1337-1345
- 41 Bisovsky S, Richter H, Fitscha P et al.. Postprandial hyperlipemia does not inhibit platelet aggregation. Prostaglandins Leukot Essent Fatty Acids. 1992; 47 331-332
- 42 Freese R, Mutanen M. Postprandial changes in platelet function and coagulation factors after high-fat meals with different fatty acid compositions. Eur J Clin Nutr. 1995; 49 658-664
- 43 Sinzinger H, Pirich C, Fitscha P, O'Grady J. Enhanced in-vitro platelet aggregability during postprandial hyperlipidaemia. Lancet. 1993; 341 48
- 44 Broijersen A, Karpe F, Hamsten A et al.. Alimentary lipemia enhances the membrane expression of platelet P-selectin without affecting other markers of platelet activation. Atherosclerosis. 1998; 137 107-113
- 45 Moor E, Silveira A, van't Hooft F et al.. Coagulation factor VII mass and activity in young men with myocardial infarction at a young age. Role of plasma lipoproteins and factor VII genotype. Arterioscler Thromb Vasc Biol . 1995; 15 655-64
- 46 Silveira A, Karpe F, Blomback M et al.. Activation of coagulation factor VII during alimentary lipemia. Arterioscler Thromb. 1994; 14 60-69
- 47 Hamsten A, de Faire U, Walldius G et al.. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet. 1987; 2 3-9
- 48 Asplund-Carlson A, Hamsten A, Wiman B et al.. Relationship between plasma plasminogen activator inhibitor-1 activity and VLDL triglyceride concentration, insulin levels and insulin sensitivity: studies in randomly selected normo- and hypertriglyceridaemic men. Diabetologia. 1993; 36 817-825
- 49 Eriksson P, Nilsson L, Karpe F et al.. Very-low-density lipoprotein response element in the promoter region of the human plasminogen activator inhibitor-1 gene implicated in the impaired fibrinolysis of hypertriglyceridemia. Arterioscler Thromb Vasc Biol. 1998; 18 20-26
- 50 Gordon T, Castelli W P, Hjortland M C et al.. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med. 1977; 62 707-714
- 51 Badimon J J, Badimon L, Galvez A et al.. High density lipoprotein plasma fractions inhibit aortic fatty streaks in cholesterol-fed rabbits. Lab Invest. 1989; 60 455-461
- 52 Nissen S E, Tsunoda T, Tuzcu E M et al.. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA. 2003; 290 2292-2300
- 53 Spieker L E, Sudano I, Hurlimann D et al.. High-density lipoprotein restores endothelial function in hypercholesterolemic men. Circulation. 2002; 105 1399-1402
- 54 Bisoendial R J, Hovingh G K, Levels J H et al.. Restoration of endothelial function by increasing high-density lipoprotein in subjects with isolated low high-density lipoprotein. Circulation. 2003; 107 2944-2948
- 55 Parthasarathy S, Barnett J, Fong L G. High-density lipoprotein inhibits the oxidative modification of low-density lipoprotein. Biochim Biophys Acta. 1990; 1044 275-283
- 56 Matsuda Y, Hirata K, Inoue N et al.. High density lipoprotein reverses inhibitory effect of oxidized low density lipoprotein on endothelium-dependent arterial relaxation. Circ Res. 1993; 72 1103-1109
- 57 Mackness M I, Harty D, Bhatnagar D et al.. Serum paraoxonase activity in familial hypercholesterolaemia and insulin-dependent diabetes mellitus. Atherosclerosis. 1991; 86 193-199
- 58 Ou J, Geiger T, Ou Z et al.. AP-4F, antennapedia peptide linked to an amphipathic alpha helical peptide, increases the efficiency of Lipofectamine-mediated gene transfection in endothelial cells. Biochem Biophys Res Commun. 2003; 305 605-610
- 59 Navab M, Imes S S, Hama S Y et al.. Monocyte transmigration induced by modification of low density lipoprotein in cocultures of human aortic wall cells is due to induction of monocyte chemotactic protein 1 synthesis and is abolished by high density lipoprotein. J Clin Invest. 1991; 88 2039-2046
- 60 Barter P J, Baker P W, Rye K A. Effect of high-density lipoproteins on the expression of adhesion molecules in endothelial cells. Curr Opin Lipidol. 2002; 13 285-288
- 61 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
- 62 Cockerill G W, Huehns T Y, Weerasinghe A et al.. Elevation of plasma high-density lipoprotein concentration reduces interleukin-1-induced expression of E-selectin in an in vivo model of acute inflammation. Circulation. 2001; 103 108-112
- 63 Rong J X, Li J, Reis E D et al.. Elevating high-density lipoprotein cholesterol in apolipoprotein E-deficient mice remodels advanced atherosclerotic lesions by decreasing macrophage and increasing smooth muscle cell content. Circulation. 2001; 104 2447-2452
- 64 Shah P K, 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. Potential implications for acute plaque stabilization. Circulation. 2001; 103 3047-3050
- 65 Naqvi T Z, Shah P K, Ivey P A et al.. Evidence that high-density lipoprotein cholesterol is an independent predictor of acute platelet-dependent thrombus formation. Am J Cardiol. 1999; 84 1011-1017
- 66 Nofer J R, Kehrel B, Fobker M et al.. HDL and arteriosclerosis: beyond reverse cholesterol transport. Atherosclerosis. 2002; 161 1-16
- 67 Rosenson R S, Lowe G D. Effects of lipids and lipoproteins on thrombosis and rheology. Atherosclerosis. 1998; 140 271-280
- 68 Carson S D. Plasma high density lipoproteins inhibit the activation of coagulation factor X by factor VIIa and tissue factor. FEBS Lett. 1981; 132 37-40
- 69 Epand R M, Stafford A, Leon B et al.. HDL and apolipoprotein A-I protect erythrocytes against the generation of procoagulant activity. Arterioscler Thromb. 1994; 14 1775-1783
- 70 Griffin J H, Kojima K, Banka C L et al.. High-density lipoprotein enhancement of anticoagulant activities of plasma protein S and activated protein C. J Clin Invest. 1999; 103 219-227
- 71 Ren S, Shen G X. Impact of antioxidants and HDL on glycated LDL-induced generation of fibrinolytic regulators from vascular endothelial cells. Arterioscler Thromb Vasc Biol. 2000; 20 1688-1693
- 72 Lamarche B, Tchernof A, Moorjani S et al.. Small, dense low-density lipoprotein particles as a predictor of the risk of ischemic heart disease in men. Prospective results from the Quebec Cardiovascular Study. Circulation. 1997; 95 69-75
- 73 Bjornheden T, Babyi A, Bondjers G et al.. Accumulation of lipoprotein fractions and subfractions in the arterial wall, determined in an in vitro perfusion system. Atherosclerosis. 1996; 123 43-56
- 74 Anber V, Millar J S, McConnell M et al.. Interaction of very-low-density, intermediate-density, and low-density lipoproteins with human arterial wall proteoglycans. Arterioscler Thromb Vasc Biol. 1997; 17 2507-2514
- 75 Tribble D L, Holl L G, Wood P D et al.. Variations in oxidative susceptibility among six low density lipoprotein subfractions of differing density and particle size. Atherosclerosis. 1992; 93 189-199
- 76 Packard C J, Shepherd J. Lipoprotein heterogeneity and apolipoprotein B metabolism. Arterioscler Thromb Vasc Biol. 1997; 17 3542-3556
- 77 Patsch J R, Miesenbock G, Hopferwieser T et al.. Relation of triglyceride metabolism and coronary artery disease. Studies in the postprandial state. Arterioscler Thromb. 1992; 12 1336-1345
- 78 Karpe F, Steiner G, Olivecrona T et al.. Metabolism of triglyceride-rich lipoproteins during alimentary lipemia. J Clin Invest. 1993; 91 748-758
- 79 Karpe F, Hellenius M L, Hamsten A. Differences in postprandial concentrations of very-low-density lipoprotein and chylomicron remnants between normotriglyceridemic and hypertriglyceridemic men with and without coronary heart disease. Metabolism. 1999; 48 301-307
- 80 Karpe F. Postprandial lipoprotein metabolism and atherosclerosis. J Intern Med. 1999; 246 341-355
- 81 Patsch W, Esterbauer H, Foger B et al.. Postprandial lipemia and coronary risk. Curr Atheroscler Rep. 2000; 2 232-242
- 82 Karpe F, de Faire U, Mercuri M et al.. Magnitude of alimentary lipemia is related to intima-media thickness of the common carotid artery in middle-aged men. Atherosclerosis. 1998; 141 307-314
- 83 Eberly L E, Stamler J, Neaton J D. Relation of triglyceride levels, fasting and nonfasting, to fatal and nonfatal coronary heart disease. Arch Intern Med. 2003; 163 1077-1083
- 84 Ballantyne C M, Olsson A G, Cook T J et al.. Influence of low high-density lipoprotein cholesterol and elevated triglyceride on coronary heart disease events and response to simvastatin therapy in 4S. Circulation. 2001; 104 3046-3051
- 85 Takemoto M, Liao J K. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors. Arterioscler Thromb Vasc Biol. 2001; 21 1712-1719
- 86 Plutzky J. Peroxisome proliferator-activated receptors in vascular biology and atherosclerosis: emerging insights for evolving paradigms. Curr Atheroscler Rep. 2000; 2 327-335
- 87 The DAIS Study Group . Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomised study. Lancet. 2001; 357 905-910
- 88 Wang T D, Chen W J, Lin J W et al.. Efficacy of fenofibrate and simvastatin on endothelial function and inflammatory markers in patients with combined hyperlipidemia: relations with baseline lipid profiles. Atherosclerosis. 2003; 170 315-323
- 89 Frick M H, Elo O, Haapa K et al.. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med. 1987; 317 1237-1245
- 90 The BIP Study Group . Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: the Bezafibrate Infarction Prevention (BIP) study. Circulation. 2000; 102 21-27
- 91 Frick M H, Manninen V, Huttunen J K et al.. HDL-cholesterol as a risk factor in coronary heart disease. An update of the Helsinki Heart Study. Drugs. 1990; 40 7-12
- 92 Tenkanen L, Manttari M, Manninen V. Some coronary risk factors related to the insulin resistance syndrome and treatment with gemfibrozil. Experience from the Helsinki Heart Study. Circulation. 1995; 92 1779-1785
- 93 Herz M, Johns D, Reviriego J et al.. A randomized, double-blind, placebo-controlled, clinical trial of the effects of pioglitazone on glycemic control and dyslipidemia in oral antihyperglycemic medication-naive patients with type 2 diabetes mellitus. Clin Ther. 2003; 25 1074-1095
- 94 Rosenson R S. Antiatherothrombotic effects of nicotinic acid. Atherosclerosis. 2003; 171 87-96
- 95 Canner P L, Berge K G, Wenger N K et al.. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol. 1986; 8 1245-1255
- 96 Clofibrate and niacin in coronary heart disease. JAMA. 1975; 231 360-81
- 97 Brown B G, Zhao X Q, Chait A et al.. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001; 345 1583-1592
- 98 Morgan J M, Capuzzi D M, Guyton J R. A new extended-release niacin (Niaspan): efficacy, tolerability, and safety in hypercholesterolemic patients. Am J Cardiol . 1998; 82 29U-34U , discussion 39U-41U
- 99 Moriyama Y, Okamura T, Inazu A et al.. A low prevalence of coronary heart disease among subjects with increased high-density lipoprotein cholesterol levels, including those with plasma cholesteryl ester transfer protein deficiency. Prev Med. 1998; 27 659-667
- 100 Barter P J, Brewer Jr H B, Chapman M J et al.. Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis. Arterioscler Thromb Vasc Biol. 2003; 23 160-167
- 101 de Grooth G J, Kuivenhoven J A, Stalenhoef A F et al.. Efficacy and safety of a novel cholesteryl ester transfer protein inhibitor, JTT-705, in humans: a randomized phase II dose-response study. Circulation. 2002; 105 2159-2165
Pia LundmanM.D. Ph.D.
Cardiology Unit, Division of Medicine, Karolinska Institutet
Danderyd Hospital, SE-182, 88 Stockholm,Sweden