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Pharmacomodulation of High-Density Lipoprotein Metabolism as a Therapeutic Intervention for Atherosclerotic Disease

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Abstract

The high-density lipoproteins (HDLs) are produced by the liver and small intestine as well as on the surface of lipid-enriched macrophages in the subendothelial space of arterial walls. Unlike the apo B100-containing lipoproteins, the HDLs are uniquely antiatherogenic. Based on prospective observational studies performed throughout the world, there is a consistent inverse relationship between serum levels of HDLs and risk for cardiovascular events: low levels of high-density lipoprotein-cholesterol (HDL-C) are associated with increased risk, whereas high levels are usually associated with reduced risk for myocardial infarction, ischemic stroke, and cardiovascular mortality. Post hoc analyses of a number of studies using statins and fibrates have shown that raising serum HDL-C correlates with a reduction in risk for cardiovascular morbidity and mortality. Given these observations, enormous resources are being committed to the development of novel means by which to pharmacologically increase rates of HDL biosynthesis, modulate the functionality of HDL, and to promote reverse cholesterol transport with intravenous infusions of HDL particles.

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Abbreviations

ERASE:

Effect of rHDL on Atherosclerosis Safety and Efficacy

HPS2-THRIVE:

Treatment of High-Density Lipoprotein to Reduce the Incidence of Vascular Events

ILLUMINATE:

Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events

ILLUSTRATE:

Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation

References

Papers of particular interest, published recently, have been highlighted as follows: • Of importance •• Of major importance

  1. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults003A Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001, 285:2486–2497.

    Article  Google Scholar 

  2. Psaty BM, Anderson M, Kronmal RA, et al.: The association between lipid levels and the risks of incident myocardial infarction, stroke, and total mortality: the Cardiovascular Health Study. J Am Geriatr Soc 2004, 52:1639–1647.

    Article  PubMed  Google Scholar 

  3. Castelli WP: Cholesterol and lipids in the risk of coronary artery disease—the Framingham Heart Study. Can J Cardiol 1988, 4:5A–10A.

    PubMed  Google Scholar 

  4. Walldius G, Jungner I, Holme I, et al.: High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study. Lancet 2001, 358:2026–2033.

    Article  CAS  PubMed  Google Scholar 

  5. •• Cui Y, Watson DJ, Girman CJ, et al.: Effects of increasing high-density lipoprotein cholesterol and decreasing low-density lipoprotein cholesterol on the incidence of first acute coronary events (from the Air Force/Texas Coronary Atherosclerosis Prevention Study). Am J Cardiol 2009, 104:829–834. This is an important post hoc analysis from the AFCAPS/TexCAPS trial demonstrating that even a minimal increase in HDL-C correlates with significant cardiovascular risk reduction in the primary care setting.

    Article  CAS  PubMed  Google Scholar 

  6. Ballantyne CM, Herd JA, Ferlic LL, et al.: Influence of low HDL on progression of coronary artery disease and response to fluvastatin therapy. Circulation 1999, 99:736–743.

    CAS  PubMed  Google Scholar 

  7. Goldenberg I, Goldbourt U, Boyko V, et al.: Relation between on-treatment increments in serum high-density lipoprotein cholesterol levels and cardiac mortality in patients with coronary heart disease (from the Bezafibrate Infarction Prevention trial). Am J Cardiol 2006, 97:466–471.

    Article  CAS  PubMed  Google Scholar 

  8. Robins SJ: Targeting low high-density lipoprotein cholesterol for therapy: lessons from the Veterans Affairs High-density Lipoprotein Intervention Trial. Am J Cardiol 2001, 88:19N–23N.

    Article  CAS  PubMed  Google Scholar 

  9. Ballantyne CM, Raichlen JS, Nicholls SJ, et al.: Effect of rosuvastatin therapy on coronary artery stenoses assessed by quantitative coronary angiography: a study to evaluate the effect of rosuvastatin on intravascular ultrasound-derived coronary atheroma burden. Circulation 2008, 117:2458–2466.

    Article  CAS  PubMed  Google Scholar 

  10. •• Nicholls SJ, Tuzcu EM, Sipahi I, et al.: Statins, high-density lipoprotein cholesterol, and regression of coronary atherosclerosis. JAMA 2007, 297:499–508. This is a landmark analysis showing that coronary atheroma regression detected by IVUS is dependent on a coupling of LDL-C reduction and HDL-C elevation.

    Article  CAS  PubMed  Google Scholar 

  11. Brown B, Zhao X, Cheung M: Should both HDL-C and LDL-C be targets for lipid therapy? A review of current evidence. J Clin Lipidol 2007, 1:88–94.

    Article  Google Scholar 

  12. •• Vaisar T, Pennathur S, Green PS, et al.: Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL. J Clin Invest 2007, 117:746–756. This is a seminal study revealing the enormous complexity of the HDL proteosome.

    Article  CAS  PubMed  Google Scholar 

  13. Toth PP: Reverse cholesterol transport: high-density lipoprotein’s magnificent mile. Curr Atheroscler Rep 2003, 5:386–393.

    Article  PubMed  Google Scholar 

  14. Nofer JR, Assmann G: Atheroprotective effects of high-density lipoprotein-associated lysosphingolipids. Trends Cardiovasc Med 2005, 15:265–271.

    Article  CAS  PubMed  Google Scholar 

  15. Nofer JR, Levkau B, Wolinska I, et al.: Suppression of endothelial cell apoptosis by high density lipoproteins (HDL) and HDL-associated lysosphingolipids. J Biol Chem 2001, 276:34480–34485.

    Article  CAS  PubMed  Google Scholar 

  16. Nofer JR, van der Giet M, Tolle M, et al.: HDL induces NO-dependent vasorelaxation via the lysophospholipid receptor S1P3. J Clin Invest 2004, 113:569–581.

    CAS  PubMed  Google Scholar 

  17. Barter P, Gotto AM, LaRosa JC, et al.: HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med 2007, 357:1301–1310.

    Article  CAS  PubMed  Google Scholar 

  18. • deGoma EM, Leeper NJ, Heidenreich PA: Clinical significance of high-density lipoprotein cholesterol in patients with low low-density lipoprotein cholesterol. J Am Coll Cardiol 2008, 51:49–55. This is an important study that demonstrated that even with LDL-C less than 60 mg/dL, a low serum level of HDL-C was associated with increased risk for CAD-related events.

    Article  CAS  PubMed  Google Scholar 

  19. Barter PJ, Kastelein JJ: Targeting cholesteryl ester transfer protein for the prevention and management of cardiovascular disease. J Amer Coll Cardiol 2006, 47:492–499.

    Article  CAS  Google Scholar 

  20. Nissen SE, Tardif JC, Nicholls SJ, et al.: Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med 2007, 356:1304–1316.

    Article  CAS  PubMed  Google Scholar 

  21. Nicholls SJ, Tuzcu EM, Brennan DM, et al.: Cholesteryl ester transfer protein inhibition, high-density lipoprotein raising, and progression of coronary atherosclerosis: insights from ILLUSTRATE (Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation). Circulation 2008, 118:2506–2514.

    Article  CAS  PubMed  Google Scholar 

  22. Kastelein JJ, van Leuven SI, Burgess L, et al.: Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia. N Engl J Med 2007, 356:1620–1630.

    Article  CAS  PubMed  Google Scholar 

  23. Bots ML, Visseren FL, Evans GW, et al.: Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial. Lancet 2007, 370:153–160.

    Article  CAS  PubMed  Google Scholar 

  24. Barter PJ, Caulfield M, Eriksson M, et al.: Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007, 357:2109–2122.

    Article  CAS  PubMed  Google Scholar 

  25. Yvan-Charvet L, Matsuura F, Wang N, et al.: Inhibition of cholesteryl ester transfer protein by torcetrapib modestly increases macrophage cholesterol efflux to HDL. Arterioscler Thromb Vasc Biol 2007, 27:1132–1138.

    Article  CAS  PubMed  Google Scholar 

  26. Stein EA, Stroes ES, Steiner G, et al.: Safety and tolerability of dalcetrapib. Am J Cardiol 2009, 104:82–91.

    Article  CAS  PubMed  Google Scholar 

  27. Krishna R, Anderson MS, Bergman AJ, et al.: Effect of the cholesteryl ester transfer protein inhibitor, anacetrapib, on lipoproteins in patients with dyslipidaemia and on 24-h ambulatory blood pressure in healthy individuals: two double-blind, randomised placebo-controlled phase I studies. Lancet 2007, 370:1907–1914.

    Article  CAS  PubMed  Google Scholar 

  28. Badimon JJ, Badimon L, Fuster V: Regression of atherosclerotic lesions by high density lipoprotein plasma fraction in the cholesterol-fed rabbit. J Clin Invest 1990, 85:1234–1241.

    Article  CAS  PubMed  Google Scholar 

  29. Ameli S, Hultgardh-Nilsson A, Cercek B, et al.: Recombinant apolipoprotein A-I Milano reduces intimal thickening after balloon injury in hypercholesterolemic rabbits. Circulation 1994, 90:1935–1941.

    CAS  PubMed  Google Scholar 

  30. Tangirala RK, Tsukamoto K, Chun SH, et al.: Regression of atherosclerosis induced by liver-directed gene transfer of apolipoprotein A-I in mice. Circulation 1999, 100:1816–1822.

    CAS  PubMed  Google Scholar 

  31. Nissen SE, Tsunoda T, Tuzcu EM, 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.

    Article  CAS  PubMed  Google Scholar 

  32. Tardif JC, Gregoire J, L’Allier PL, et al.: Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial. JAMA 2007, 297:1675–1682.

    Article  PubMed  Google Scholar 

  33. Sacks FM, Rudel LL, Conner A, et al.: Selective delipidation of plasma HDL enhances reverse cholesterol transport in vivo. J Lipid Res 2009, 50:894–907.

    Article  CAS  PubMed  Google Scholar 

  34. •• Bailey D, Jahagirdar R, Gordon A, et al.: RVX-208: a small molecule that increases apolipoprotein A-I and high-density lipoprotein cholesterol in vitro and in vivo. J Am Coll Cardiol 2010, 55:2580–2589. This paper discusses a remarkable leap in apo A-I therapeutics demonstrating that an orally bioavailable small molecule drug stimulates hepatic apo A-I expression, macrophage cholesterol efflux, and ndHDL formation in humans.

    Article  CAS  PubMed  Google Scholar 

  35. Nishizawa T, Kitayama K, Wakabayashi K, et al.: A novel compound, R-138329, increases plasma HDL cholesterol via inhibition of scavenger receptor BI-mediated selective lipid uptake. Atherosclerosis 2007, 194:300–308.

    Article  CAS  PubMed  Google Scholar 

  36. Trigatti B, Covey S, Rizvi A: Scavenger receptor class B type I in high-density lipoprotein metabolism, atherosclerosis and heart disease: lessons from gene-targeted mice. Biochem Soc Trans 2004, 32(Pt 1):116–120.

    Article  CAS  PubMed  Google Scholar 

  37. Staels B, Fruchart JC: Therapeutic roles of peroxisome proliferator-activated receptor agonists. Diabetes 2005, 54:2460–2470.

    Article  CAS  PubMed  Google Scholar 

  38. Chinetti G, Lestavel S, Bocher V, et al.: PPAR-alpha and PPAR-gamma activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway. Nat Med 2001, 7:53–58.

    Article  CAS  PubMed  Google Scholar 

  39. Chinetti-Gbaguidi G, Rigamonti E, Helin L, et al.: Peroxisome proliferator-activated receptor alpha controls cellular cholesterol trafficking in macrophages. J Lipid Res 2005, 46:2717–2725.

    Article  CAS  PubMed  Google Scholar 

  40. Fruchart JC: Novel peroxisome proliferator activated receptor-alpha agonists. Am J Cardiol 2007, 100:n41–n46.

    Article  PubMed  Google Scholar 

  41. Naik SU, Wang X, Da Silva JS, et al.: Pharmacological activation of liver X receptors promotes reverse cholesterol transport in vivo. Circulation 2006, 113:90–97.

    Article  CAS  PubMed  Google Scholar 

  42. Pal M, Pillarisetti S: HDL elevators and mimetics—emerging therapies for atherosclerosis. Cardiovasc Hematol Agents Med Chem 2007, 5:55–66.

    CAS  PubMed  Google Scholar 

  43. Li AC, Glass CK: PPAR- and LXR-dependent pathways controlling lipid metabolism and the development of atherosclerosis. J Lipid Res 2004, 45:2161–2173.

    Article  CAS  PubMed  Google Scholar 

  44. Segrest JP, Li L, Anantharamaiah GM, et al.: Structure and function of apolipoprotein A-I and high-density lipoprotein. Curr Opin Lipidol 2000, 11:105–115.

    Article  CAS  PubMed  Google Scholar 

  45. Li X, Chyu KY, Faria Neto JR, et al.: Differential effects of apolipoprotein A-I-mimetic peptide on evolving and established atherosclerosis in apolipoprotein E-null mice. Circulation 2004, 110:1701–1705.

    Article  CAS  PubMed  Google Scholar 

  46. Navab M, Anantharamaiah GM, Reddy ST, et al.: Apolipoprotein A-I mimetic peptides. Arterioscler Thromb Vasc Biol 2005, 25:1325–1331.

    Article  CAS  PubMed  Google Scholar 

  47. Anantharamaiah GM, Mishra VK, Garber DW, et al.: Structural requirements for antioxidative and anti-inflammatory properties of apolipoprotein A-I mimetic peptides. J Lipid Res 2007, 48:1915–1923.

    Article  CAS  PubMed  Google Scholar 

  48. Clofibrate and niacin in coronary heart disease [no authors listed]. JAMA 1975, 231:360–381.

  49. Brown BG, Zhao XQ, 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.

    Article  CAS  PubMed  Google Scholar 

  50. Cheng K, Wu TJ, Wu KK, et al.: Antagonism of the prostaglandin D2 receptor 1 suppresses nicotinic acid-induced vasodilation in mice and humans. Proc Natl Acad Sci U S A 2006, 103:6682–6687.

    Article  CAS  PubMed  Google Scholar 

  51. • Paolini JF, Mitchel YB, Reyes R, et al.: Effects of laropiprant on nicotinic acid-induced flushing in patients with dyslipidemia. Am J Cardiol 2008, 101:625–630. Laropiprant effectively reduces niacin-induced flushing and significantly increases compliance with niacin therapy without blunting the therapeutic efficacy of the drug on lipid parameters.

    Article  CAS  PubMed  Google Scholar 

  52. Maccubbin D, Bays HE, Olsson AG, et al.: Lipid-modifying efficacy and tolerability of extended-release niacin/laropiprant in patients with primary hypercholesterolaemia or mixed dyslipidaemia. Int J Clin Pract 2008, 62:1959–1970.

    Article  CAS  PubMed  Google Scholar 

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Disclosure

Peter P. Toth has been a consultant for Abbott, AstraZeneca, Kowa, and Merck & Co. He has also been on the speakers’ bureau for Abbott, AstraZeneca, GlaxoSmithKline, Merck & Co., Pfizer, and Takeda.

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Toth, P.P. Pharmacomodulation of High-Density Lipoprotein Metabolism as a Therapeutic Intervention for Atherosclerotic Disease. Curr Cardiol Rep 12, 481–487 (2010). https://doi.org/10.1007/s11886-010-0136-3

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