High-density lipoprotein and atherosclerosis regression: Evidence from preclinical and clinical studies

Circulation Research

Volumn 114, Issue 1, 2014, Pages 205-213

  Feig, Jonathan E ^a,c   Hewing, Bernd ^a,d   Smith, Jonathan D ^b   Hazen, Stanley L ^b   Fisher, Edward A ^a  

^a NEW YORK UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE   (United States)

^c MOUNT SINAI SCHOOL OF MEDICINE   (United States)

^d CHARITÉ UNIVERSITÄTSMEDIZIN BERLIN   (Germany)

Author keywords

atherosclerosis; cholesterol; coronary artery disease; HDL; mice; regression

Indexed keywords

ANTILIPEMIC AGENT; APOLIPOPROTEIN A1; APOLIPOPROTEIN B; CHOLESTEROL ESTER TRANSFER PROTEIN; COLLAGEN; HIGH DENSITY LIPOPROTEIN; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; LIPID; LOW DENSITY LIPOPROTEIN; PHOSPHOLIPID; TRIACYLGLYCEROL; VASCULAR CELL ADHESION MOLECULE 1;

AORTA ATHEROSCLEROSIS; ATHERECTOMY; ATHEROGENESIS; ATHEROMA; ATHEROSCLEROSIS; ATHEROSCLEROTIC PLAQUE; CARDIOVASCULAR DISEASE; CARDIOVASCULAR RISK; CHOLESTEROL BLOOD LEVEL; CHOLESTEROL TRANSPORT; CLINICAL STUDY; CORONARY ARTERY ATHEROSCLEROSIS; HUMAN; INFLAMMATION; LIPID STORAGE; MACROPHAGE; NONHUMAN; PRIORITY JOURNAL; REMISSION; REVIEW;

EID: 84892938632     PISSN: 00097330     EISSN: 15244571     Source Type: Journal    
DOI: 10.1161/CIRCRESAHA.114.300760     Document Type: Review

References (85)

1. Castelli WP, Garrison RJ, Wilson PW, Abbott RD, Kalousdian S, Kannel WB. Incidence of coronary heart disease and lipoprotein cholesterol levels. The Framingham Study. JAMA. 1986;256:2835-2838.
2. Franceschini G. Epidemiologic evidence for high-density lipoprotein cholesterol as a risk factor for coronary artery disease. Am J Cardiol. 2001;88:9N-13N.
3. Gordon DJ, Rifkind BM. High-density lipoprotein-the clinical implications of recent studies. N Engl J Med. 1989;321:1311-1316.
4. Miller NE, Miller GJ. Letter: High-density lipoprotein and atherosclerosis. Lancet. 1975;1:1033.
5. Banka CL. High density lipoprotein and lipoprotein oxidation. Curr Opin Lipidol. 1996;7:139-142.
6. Fielding CJ, Fielding PE. Molecular physiology of reverse cholesterol transport. J Lipid Res. 1995;36:211-228.
7. Feig JE, Shamir R, Fisher EA. Atheroprotective effects of HDL: beyond reverse cholesterol transport. Curr Drug Targets. 2008;9:196-203.
8. Stein Y, Stein O. Does therapeutic intervention achieve slowing of progression or bona fde regression of atherosclerotic lesions? Arterioscler Thromb Vasc Biol. 2001;21:183-188.
9. Khera AV, Cuchel M, de la Llera-Moya M, Rodrigues A, Burke MF, Jafri K, French BC, Phillips JA, Mucksavage ML, Wilensky RL, Mohler ER, Rothblat GH, Rader DJ. Cholesterol effux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med. 2011;364:127-135.
10. Voight BF, Peloso GM, Orho-Melander M, et al. Plasma HDL cholesterol and risk of myocardial infarction: a Mendelian randomisation study. Lancet. 2012;380:572-580.
11. Boden WE, Probstfeld JL, Anderson T, Chaitman BR, 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;365:2255-2267
12. Schwartz GG, Olsson AG, Abt M, et al.; dal-OUTCOMES Investigators. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012;367:2089-2099.
13. Hewing B, Moore KJ, Fisher EA. HDL and cardiovascular risk: time to call the plumber? Circ Res. 2012;111:1117-1120.
14. Williams KJ, Feig JE, Fisher EA. Cellular and molecular mechanisms for rapid regression of atherosclerosis: from bench top to potentially achievable clinical goal. Curr Opin Lipidol. 2007;18:443-450.
15. Williams KJ, Feig JE, Fisher EA. Rapid regression of atherosclerosis: insights from the clinical and experimental literature. Nat Clin Pract Cardiovasc Med. 2008;5:91-102.
16. Friedman M, Byers SO, Rosenman RH. Resolution of aortic atherosclerotic infltration in the rabbit by phosphatide infusion. Proc Soc Exp Biol Med. 1957;95:586-588.
17. 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.
18. Williams KJ, Werth VP, Wolff JA. Intravenously administered lecithin liposomes: a synthetic antiatherogenic lipid particle. Perspect Biol Med. 1984;27:417-431.
19. Armstrong ML, Warner ED, Connor WE. Regression of coronary athero-matosis in rhesus monkeys. Circ Res. 1970;27:59-67.
20. Armstrong ML. Evidence of regression of atherosclerosis in primates and man. Postgrad Med J. 1976;52:456-461.
21. Wissler RW, Vesselinovitch D. Studies of regression of advanced atherosclerosis in experimental animals and man. Ann N Y Acad Sci. 1976;275:363-378.
22. 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.
23. Miyazaki A, Sakuma S, Morikawa W, Takiue T, Miake F, Terano T, Sakai M, Hakamata H, Sakamoto Y, Natio M. Intravenous injection of rabbit apolipoprotein A-I inhibits the progression of atherosclerosis in cholesterol-fed rabbits. Arterioscler Thromb Vasc Biol. 1995;15:1882-1888.
24. Breslow JL. Transgenic mouse models of lipoprotein metabolism and atherosclerosis. Proc Natl Acad Sci USA. 1993;90:8314-8318.
25. Breslow JL. Mouse models of atherosclerosis. Science. 1996;272:685-688.
26. Plump AS, Scott CJ, Breslow JL. Human apolipoprotein A-I gene expression increases high density lipoprotein and suppresses atherosclerosis in the apolipoprotein E-defcient mouse. Proc Natl Acad Sci USA. 1994;91:9607-9611.
27. Pászty C, Maeda N, Verstuyft J, Rubin EM. Apolipoprotein AI transgene corrects apolipoprotein E defciency-induced atherosclerosis in mice. J Clin Invest. 1994;94:899-903.
28. Tangirala RK, Tsukamoto K, Chun SH, Usher D, Puré E, Rader DJ. Regression of atherosclerosis induced by liver-directed gene transfer of apolipoprotein A-I in mice. Circulation. 1999;100:1816-1822.
29. Li R, Chao H, Ko KW, Cormier S, Dieker C, Nour EA, Wang S, Chan L, Oka K. Gene therapy targeting LDL cholesterol but not HDL cholesterol induces regression of advanced atherosclerosis in a mouse model of familial hypercholesterolemia. J Genet Syndr Gene Ther. 2011;2:106.
30. Rong JX, Li J, Reis ED, Choudhury RP, Dansky HM, Elmalem VI, Fallon JT, Breslow JL, Fisher EA. Elevating high-density lipoprotein cholesterol in apolipoprotein E-defcient mice remodels advanced atherosclerotic lesions by decreasing macrophage and increasing smooth muscle cell content. Circulation. 2001;104:2447-2452.
31. Feig JE, Rong JX, Shamir R, Sanson M, Vengrenyuk Y, Liu J, Rayner K, Moore K, Garabedian M, Fisher EA. HDL promotes rapid atherosclerosis regression in mice and alters infammatory properties of plaque monocyte-derived cells. Proc Natl Acad Sci USA. 2011;108:7166-7171.
32. Shah PK, Yano J, Reyes O, Chyu KY, Kaul S, Bisgaier CL, Drake S, Cercek B. High-dose recombinant apolipoprotein A-I(milano) mobilizes tissue cholesterol and rapidly reduces plaque lipid and macrophage content in apolipoprotein e-defcient mice. Potential implications for acute plaque stabilization. Circulation. 2001;103:3047-3050.
33. 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-defcient mouse in a novel transplantation model. J Vasc Surg. 2001;34:541-547
34. Chereshnev I, Trogan E, Omerhodzic S, Itskovich V, Aguinaldo JG, Fayad ZA, Fisher EA, Reis ED. Mouse model of heterotopic aortic arch transplantation. J Surg Res. 2003;111:171-176.
35. 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 USA. 2004;101:11779-11784.
36. Trogan E, Fayad ZA, Itskovich VV, Aguinaldo JG, Mani V, Fallon JT, Chereshnev I, Fisher EA. Serial studies of mouse atherosclerosis by in vivo magnetic resonance imaging detect lesion regression after correction of dyslipidemia. Arterioscler Thromb Vasc Biol. 2004;24:1714-1719.
37. Trogan E, Feig JE, Dogan S, Rothblat GH, Angeli V, Tacke F, Randolph GJ, Fisher EA. Gene expression changes in foam cells and the role of chemokine receptor CCR7 during atherosclerosis regression in ApoE-defcient mice. Proc Natl Acad Sci USA. 2006;103:3781-3786.
38. Förster R, Schubel A, Breitfeld D, Kremmer E, Renner-Müller I, Wolf E, Lipp M. CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell. 1999;99:23-33.
39. Feig JE, Shamir R, Joaquin V, Grauer L, Fisher EA. Apoai is required for the regression of atherosclerosis and is a potent regulator of plaque mono-cyte-derived emigration and infammatory state. Arterioscler Thromb Vasc Biol. 2009;29:e13.
40. Feig JE, Shang Y, Rotllan N, Vengrenyuk Y, Wu C, Shamir R, Torra IP, Fernandez-Hernando C, Fisher EA, Garabedian MJ. Statins promote the regression of atherosclerosis via activation of the CCR7-dependent emigration pathway in macrophages. PLoS One. 2011;6:e28534.
41. Yvan-Charvet L, Pagler T, Gautier EL, Avagyan S, Siry RL, Han S, Welch CL, Wang N, Randolph GJ, Snoeck HW, Tall AR. ATP-binding cassette transporters and HDL suppress hematopoietic stem cell proliferation. Science. 2010;328:1689-1693.
42. Dansky HM, Charlton SA, Barlow CB, Tamminen M, Smith JD, Frank JS, Breslow JL. Apo A-I inhibits foam cell formation in Apo E-defcient mice after monocyte adherence to endothelium. J Clin Invest. 1999;104:31-39.
43. Potteaux S, Gautier EL, Hutchison SB, van Rooijen N, Rader DJ, Thomas MJ, Sorci-Thomas MG, Randolph GJ. Suppressed monocyte recruitment drives macrophage removal from atherosclerotic plaques of Apoe-/-mice during disease regression. J Clin Invest. 2011;121:2025-2036.
44. Tabas I. Macrophage death and defective infammation resolution in atherosclerosis. Nat Rev Immunol. 2010;10:36-46.
45. Gordon S, Mantovani A. Diversity and plasticity of mononuclear phagocytes. Eur J Immunol. 2011;41:2470-2472.
46. Bouhlel MA, Derudas B, Rigamonti E, Dièvart R, Brozek J, Haulon S, Zawadzki C, Jude B, Torpier G, Marx N, Staels B, Chinetti-Gbaguidi G. PPARgamma activation primes human monocytes into alternative M2 mac-rophages with anti-infammatory properties. Cell Metab. 2007;6:137-143.
47. Khallou-Laschet J, Varthaman A, Fornasa G, Compain C, Gaston AT, Clement M, Dussiot M, Levillain O, Graff-Dubois S, Nicoletti A, Caligiuri G. Macrophage plasticity in experimental atherosclerosis. PLoS One. 2010;5:e8852.
48. Yvan-Charvet L, Welch C, Pagler TA, Ranalletta M, Lamkanf M, Han S, Ishibashi M, Li R, Wang N, Tall AR. Increased infammatory gene expression in ABC transporter-defcient macrophages: free cholesterol accumulation, increased signaling via toll-like receptors, and neutrophil infltration of atherosclerotic lesions. Circulation. 2008;118:1837-1847.
49. Zhu X, Lee JY, Timmins JM, Brown JM, Boudyguina E, Mulya A, Gebre AK, Willingham MC, Hiltbold EM, Mishra N, Maeda N, Parks JS. Increased cellular free cholesterol in macrophage-specifc Abca1 knockout mice enhances pro-infammatory response of macrophages. J Biol Chem. 2008;283:22930-22941.
50. Feig JE, Parathath S, Rong JX, Mick SL, Vengrenyuk Y, Grauer L, Young SG, Fisher EA. Reversal of hyperlipidemia with a genetic switch favorably affects the content and infammatory state of macrophages in atherosclerotic plaques. Circulation. 2011;123:989-998.
51. Rayner KJ, Suárez Y, Dávalos A, Parathath S, Fitzgerald ML, Tamehiro N, Fisher EA, Moore KJ, Fernández-Hernando C. MiR-33 contributes to the regulation of cholesterol homeostasis. Science. 2010;328:1570-1573.
52. Rayner KJ, Sheedy FJ, Esau CC, Hussain FN, Temel RE, Parathath S, van Gils JM, Rayner AJ, Chang AN, Suarez Y, Fernandez-Hernando C, Fisher EA, Moore KJ. Antagonism of miR-33 in mice promotes reverse cholesterol transport and regression of atherosclerosis. J Clin Invest. 2011;121:2921-2931.
53. Cardilo-Reis L, Gruber S, Schreier SM, Drechsler M, Papac-Milicevic N, Weber C, Wagner O, Stangl H, Soehnlein O, Binder CJ. Interleukin-13 protects from atherosclerosis and modulates plaque composition by skewing the macrophage phenotype. EMBO Mol Med. 2012;4:1072-1086.
54. Wolfs IM, Stoger JL, Goossens P, Pottgens C, Gijbels MJ, Wijnands E, van der Vorst EP, van Gorp P, Beckers L, Engel D, Biessen EA, Kraal G, van Die I, Donners MM, de Winther MP. Reprogramming macrophages to an anti-infammatory phenotype by helminth antigens reduces murine atherosclerosis. Faseb J. September 16, 2013. doi: 10.1096/fj.13-235911. http://www.fasebj.org/content/ early/2013/09/16/fj.13-235911.long. Accessed December 18, 2013.
55. Smythies LE, White CR, Maheshwari A, Palgunachari MN, Anantharamaiah GM, Chaddha M, Kurundkar AR, Datta G. Apolipoprotein A-I mimetic 4F alters the function of human monocyte-derived macro-phages. Am J Physiol Cell Physiol. 2010;298:C1538-C1548.
56. Odegaard JI, Chawla A. Alternative macrophage activation and metabolism. Annu Rev Pathol. 2011;6:275-297.
57. Sanson M, Distel E, Fisher EA. HDL induces the expression of the M2 macrophage markers arginase 1 and Fizz-1 in a STAT6-dependent process. PLoS One. 2013;8:e74676.
58. 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.
59. Tardif JC, Grégoire J, L'Allier PL, Ibrahim R, Lespérance J, Heinonen TM, Kouz S, Berry C, Basser R, Lavoie MA, Guertin MC, Rodés-Cabau J; Effect of rHDL on Atherosclerosis-Safety and Effcacy (ERASE) Investigators. Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial. JAMA. 2007;297:1675-1682.
60. Shaw JA, Bobik A, Murphy A, Kanellakis P, Blombery P, Mukhamedova N, Woollard K, Lyon S, Sviridov D, Dart AM. Infusion of reconstituted high-density lipoprotein leads to acute changes in human atherosclerotic plaque. Circ Res. 2008;103:1084-1091.
61. Digby JE, Ruparelia N, Choudhury RP. Niacin in cardiovascular disease: recent preclinical and clinical developments. Arterioscler Thromb Vasc Biol. 2012;32:582-588.
62. Brown G, Albers JJ, Fisher LD, Schaefer SM, Lin JT, Kaplan C, Zhao XQ, Bisson BD, Fitzpatrick VF, Dodge HT. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med. 1990;323:1289-1298.
63. Cashin-Hemphill L, Mack WJ, Pogoda JM, Sanmarco ME, Azen SP, Blankenhorn DH. Benefcial effects of colestipol-niacin on coronary atherosclerosis. A 4-year follow-up. JAMA. 1990;264:3013-3017.
64. Brown BG, Zhao XQ, Chait A, Fisher LD, Cheung MC, Morse JS, Dowdy AA, Marino EK, Bolson EL, Alaupovic P, Frohlich J, Albers JJ. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001;345:1583-1592.
65. Taylor AJ, Sullenberger LE, Lee HJ, Lee JK, Grace KA. Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins. Circulation. 2004;110:3512-3517.
66. Song WL, FitzGerald GA. Niacin, an old drug with a new twist. J Lipid Res. 2013;54:2586-2594.
67. Arai T, Wang N, Bezouevski M, Welch C, Tall AR. Decreased atherosclerosis in heterozygous low density lipoprotein receptor-defcient mice expressing the scavenger receptor BI transgene. J Biol Chem. 1999;274:2366-2371.
68. Tall AR, Yvan-Charvet L, Terasaka N, Pagler T, Wang N. HDL, ABC transporters, and cholesterol effux: implications for the treatment of atherosclerosis. Cell Metab. 2008;7:365-375.
69. Zhong S, Sharp DS, Grove JS, Bruce C, Yano K, Curb JD, Tall AR. Increased coronary heart disease in Japanese-American men with mutation in the cholesteryl ester transfer protein gene despite increased HDL levels. J Clin Invest. 1996;97:2917-2923.
70. Barter PJ, Caulfeld M, Eriksson M, et al.; ILLUMINATE Investigators. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007;357:2109-2122.
71. Barter P. Lessons learned from the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial. Am J Cardiol. 2009;104:10E-15E.
72. Nicholls SJ, Tuzcu EM, Brennan DM, Tardif JC, Nissen SE. 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.
73. Cannon CP, Shah S, Dansky HM, Davidson M, Brinton EA, Gotto AM, Stepanavage M, Liu SX, Gibbons P, Ashraf TB, Zafarino J, Mitchel Y, Barter P; Determining the Effcacy and Tolerability Investigators. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med. 2010;363:2406-2415.
74. Nicholls SJ, Brewer HB, Kastelein JJ, Krueger KA, Wang MD, Shao M, Hu B, McErlean E, Nissen SE. Effects of the CETP inhibitor eva-cetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol: a randomized controlled trial. JAMA. 2011;306:2099-2109.
75. Nicholls SJ, Tuzcu EM, Sipahi I, Grasso AW, Schoenhagen P, Hu T, Wolski K, Crowe T, Desai MY, Hazen SL, Kapadia SR, Nissen SE. Statins, high-density lipoprotein cholesterol, and regression of coronary atherosclerosis. JAMA. 2007;297:499-508.
76. Yancey PG, Bortnick AE, Kellner-Weibel G, de la Llera-Moya M, Phillips MC, Rothblat GH. Importance of different pathways of cellular cholesterol effux. Arterioscler Thromb Vasc Biol. 2003;23:712-719.
77. Asztalos BF, Roheim PS, Milani RL, Lefevre M, McNamara JR, Horvath KV, Schaefer EJ. Distribution of ApoA-I-containing HDL subpopulations in patients with coronary heart disease. Arterioscler Thromb Vasc Biol. 2000;20:2670-2676.
78. Wang X, Collins HL, Ranalletta M, Fuki IV, Billheimer JT, Rothblat GH, Tall AR, Rader DJ. Macrophage ABCA1 and ABCG1, but not SR-BI, promote macrophage reverse cholesterol transport in vivo. J Clin Invest. 2007;117:2216-2224.
79. Calabresi L, Franceschini G, Sirtori CR, De Palma A, Saresella M, Ferrante P, Taramelli D. Inhibition of VCAM-1 expression in endothelial cells by reconstituted high density lipoproteins. Biochem Biophys Res Commun. 1997;238:61-65.
80. Mineo C, Shaul PW. Role of high-density lipoprotein and scavenger receptor B type I in the promotion of endothelial repair. Trends Cardiovasc Med. 2007;17:156-161.
81. Undurti A, Huang Y, Lupica JA, Smith JD, DiDonato JA, Hazen SL. Modifcation of high density lipoprotein by myeloperoxidase generates a pro-infammatory particle. J Biol Chem. 2009;284:30825-30835.
82. Fisher EA, Feig JE, Hewing B, Hazen SL, Smith JD. High-density lipopro-tein function, dysfunction, and reverse cholesterol transport. Arterioscler Thromb Vasc Biol. 2012;32:2813-2820.
83. Didonato JA, Huang Y, Aulak KS, Even-Or O, Gerstenecker G, Gogonea V, Wu Y, Fox PL, Tang WH, Plow EF, Smith JD, Fisher EA, Hazen SL. Function and distribution of apolipoprotein A1 in the artery wall are markedly distinct from those in plasma. Circulation. 2013;128: 1644-1655.
84. Parolini C, Marchesi M, Lorenzon P, Castano M, Balconi E, Miragoli L, Chaabane L, Morisetti A, Lorusso V, Martin BJ, Bisgaier CL, Krause B, Newton RS, Sirtori CR, Chiesa G. Dose-related effects of repeated ETC-216 (recombinant apolipoprotein A-I Milano/1-palmitoyl-2-oleoyl phosphatidylcholine complexes) administrations on rabbit lipid-rich soft plaques: in vivo assessment by intravascular ultrasound and magnetic resonance imaging. J Am Coll Cardiol. 2008;51:1098-1103.
85. Cho KH. A reconstituted high density lipoprotein containing the V156E mutant of apolipoprotein A-I exhibits anti-atherosclerotic activity in Apo-E defcient mice. J Atheroscler Thromb. 2009;16:217-229.