A novel BET bromodomain inhibitor, RVX-208, shows reduction of atherosclerosis in hyperlipidemic ApoE deficient mice

Atherosclerosis

Volumn 236, Issue 1, 2014, Pages

  Jahagirdar, Ravi ^a   Zhang, Haiyan ^b   Azhar, Salman ^b   Tobin, Jennifer ^a   Attwell, Sarah ^a   Yu, Raymond ^a   Wu, Jin ^a   McLure, Kevin G ^a   Hansen, Henrik C ^a   Wagner, Gregory S ^a   Young, Peter R ^a   Srivastava, Rai Ajit K ^c   Wong, Norman C W ^a   Johansson, Jan ^a  

^a Resverlogix Corp   (Canada)

^b VA PALO ALTO HEALTH CARE SYSTEM   (United States)

^c Integrated Pharma Solutions   (United States)

Author keywords

ApoA I inducer; ApoE deficient; Atherosclerosis; BET inhibitor; Inflammation; Pre HDL; RVX 208

Indexed keywords

APOLIPOPROTEIN A1; APOLIPOPROTEIN E; CARDIOVASCULAR AGENT; GAMMA INTERFERON INDUCIBLE PROTEIN 10; HAPTOGLOBIN; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; INTERCELLULAR ADHESION MOLECULE 1; INTERLEUKIN 18; INTERLEUKIN 6; LOW DENSITY LIPOPROTEIN CHOLESTEROL; MACROPHAGE INFLAMMATORY PROTEIN 1ALPHA; MESSENGER RNA; MONOCYTE CHEMOTACTIC PROTEIN 1; RVX 208; TRIACYLGLYCEROL; UNCLASSIFIED DRUG; VASCULAR CELL ADHESION MOLECULE 1; APABETALONE; BETAINE HOMOCYSTEINE METHYLTRANSFERASE; CYTOKINE; QUINAZOLINE DERIVATIVE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIATHEROGENIC ACTIVITY; ANTIINFLAMMATORY ACTIVITY; AORTA DISEASE; ARTICLE; ATHEROSCLEROSIS; BODY WEIGHT; CHOLESTEROL BLOOD LEVEL; CONTROLLED STUDY; DIET; DISEASE COURSE; DRUG ACTIVITY; DRUG EFFECT; GENE EXPRESSION; HYPERLIPIDEMIA; IN VITRO STUDY; IN VIVO STUDY; MALE; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROPHYLAXIS; PROTEIN BINDING; TREATMENT DURATION; TRIACYLGLYCEROL BLOOD LEVEL; WESTERN DIET; ADVERSE EFFECTS; ANIMAL; ANTAGONISTS AND INHIBITORS; AORTA; AORTIC DISEASES; BLOOD; C57BL MOUSE; CELL LINE; COMPLICATION; DEFICIENCY; DIET THERAPY; DRUG EFFECTS; DRUG SCREENING; ENDOTHELIUM CELL; GENE EXPRESSION PROFILING; GENETICS; HUMAN; HYPERLIPIDEMIAS; INFLAMMATION; KNOCKOUT MOUSE; LIVER; LOW FAT DIET; METABOLISM; PATHOLOGY; U937 CELL LINE;

ANIMALS; AORTA; AORTIC DISEASES; APOLIPOPROTEIN A-I; APOLIPOPROTEINS E; ATHEROSCLEROSIS; BETAINE-HOMOCYSTEINE S-METHYLTRANSFERASE; CELL LINE; CHOLESTEROL, HDL; CHOLESTEROL, LDL; CYTOKINES; DIET, FAT-RESTRICTED; DIET, WESTERN; DRUG EVALUATION, PRECLINICAL; ENDOTHELIAL CELLS; GENE EXPRESSION PROFILING; HUMANS; HYPERLIPIDEMIAS; INFLAMMATION; LIVER; MALE; MICE; MICE, INBRED C57BL; MICE, KNOCKOUT; QUINAZOLINES; RNA, MESSENGER; U937 CELLS;

EID: 84905842525     PISSN: 00219150     EISSN: 18791484     Source Type: Journal    
DOI: 10.1016/j.atherosclerosis.2014.06.008     Document Type: Article

References (97)

1. American Heart Association HDass-u Areport from the American heart association statistics committee and stroke statistics subcommittee. Circulation 2007, 115:e69-e71.
2. Cannon C.P., Braunwald E., McCabe C.H., et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. NEngl J Med 2004, 350:1495-1504.
3. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993, 362:801-809.
4. Ross R. Atherosclerosis-an inflammatory disease. NEngl J Med 1999, 340:115-126.
5. Fonarow G.C., Watson K.E. Effective strategies for long-term statin use. Am J Cardiol 2003, 92:27i-34i.
6. Kastelein J.J. The future of lipid-lowering therapy: the big picture. Neth J Med 2003, 61:35-39.
7. Gordon 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, 74:1217-1225.
8. Linsel-Nitschke P., Tall A.R. HDL as a target in the treatment of atherosclerotic cardiovascular disease. Nat Rev Drug Discov 2005, 4:193-205.
9. Gordon D.J., Probstfield J.L., Garrison R.J., et al. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation 1989, 79:8-15.
10. Hopkins P.N., Heiss G., Ellison R.C., et al. Coronary artery disease risk in familial combined hyperlipidemia and familial hypertriglyceridemia: a case-control comparison from the National heart, lung, and blood institute family heart Study. Circulation 2003, 108:519-523.
11. Genest J.J., McNamara J.R., Salem D.N., Schaefer E.J. Prevalence of risk factors in men with premature coronary artery disease. Am J Cardiol 1991, 67:1185-1189.
12. Investigators D.A.I.S. 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.
13. 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. NEngl J Med 1987, 317:1237-1245.
14. Rubins H.B., Robins S.J., Collins D., et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs high-density lipoprotein cholesterol intervention trial study group. NEngl J Med 1999, 341:410-418.
15. Reaven G.M. Pathophysiology of insulin resistance in human disease. Physiol Rev 1995, 75:473-486.
16. Moller D.E., Kaufman K.D. Metabolic syndrome: a clinical and molecular perspective. Annu Rev Med 2005, 56:45-62.
17. Srivastava R.A., Srivastava N. Search for obesity drugs: targeting central and peripheral pathways. curr med chem - immun. Endoc Metab Agents 2004, 4:75-90.
18. Srivastava R.A., Srivastava N. High density lipoprotein, apolipoprotein A-I, and coronary artery disease. Mol Cell Biochem 2000, 209:131-144.
19. Acton S., Rigotti A., Landschulz K.T., Xu S., Hobbs H.H., Krieger M. Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science 1996, 271:518-520.
20. Van Eck M., Pennings M., Hoekstra M., Out R., Van Berkel T.J. Scavenger receptor BI and ATP-binding cassette transporter A1 in reverse cholesterol transport and atherosclerosis. Curr Opin Lipidol 2005, 16:307-315.
21. Joyce C.W., Amar M.J., Lambert G., et al. The ATP binding cassette transporter A1 (ABCA1) modulates the development of aortic atherosclerosis in C57BL/6 and apoE-knockout mice. Proc Natl Acad Sci U S A 2002, 99:407-412.
22. Srivastava N. ATP binding cassette transporter A1-key roles in cellular lipid transport and atherosclerosis. Mol Cell Biochem 2002, 237:155-164.
23. Kennedy M.A., Barrera G.C., Nakamura K., et al. ABCG1 has a critical role in mediating cholesterol efflux to HDL and preventing cellular lipid accumulation. Cell Metab 2005, 1:121-131.
24. Owen D.R., Trzupek J.D. Epigenetics drugs that do not target enzyme activity. Drug Discov Today: Technologies 2014, 12(complete)e29-e34.
25. McLure K.G., Gesner E.M., Tsujikawa L., Kharencko O.A., Attwell S., Campeau Wu, et al. An inducer of apoA-I in humans, is a bet bromodomain antagonist. PloS One 2013, 8. In Press.
26. Picaud S., Wells C., Felletar I., et al. RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain. Proc Natl Acad Sci USA 2013, 110(49):19754-19759. 10.1073/pnas.1310658110.
27. Bailey D., Jahagirdar R., Gordon A., et al. RVX-208: a small molecule that increases apolipoprotein A-I and high-density lipoprotein cholesterol invitro and invivo. JAm Coll Cardiol 2010, 55:2580-2589.
28. Plump A.S., Smith J.D., Hayek T., et al. Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell 1992, 71:343-353.
29. Zhang S.H., Reddick R.L., Piedrahita J.A., Maeda N. Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science 1992, 258:468-471.
30. Paszty C., Maeda N., Verstuyft J., Rubin E.M. Apolipoprotein AI transgene corrects apolipoprotein E deficiency-induced atherosclerosis in mice. JClin Invest 1994, 94:899-903.
31. Zadelaar S., Kleemann R., Verschuren L., et al. Mouse models for atherosclerosis and pharmaceutical modifiers. Arterioscler Thromb Vasc Biol 2007, 27:1706-1721.
32. Katnik I., Jadach J. Haptoglobin concentration in serum and other body fluids measured by comparison of its reactivity with hemoglobin and concanavalin A. Arch Immunol Ther Exp 1996, 44:45-50.
33. Altruda F., Poli V., Restagno G., Argos P., Cortese R., Silengo L. The primary structure of human hemopexin deduced from cDNA sequence: evidence for internal, repeating homology. Nucleic Acids Res 1985, 13:3841-3859.
34. Watanabe J., Grijalva V., Hama S., et al. Hemoglobin and its scavenger protein haptoglobin associate with apoA-1-containing particles and influence the inflammatory properties and function of high density lipoprotein. JBiol Chem 2009, 284:18292-18301.
35. Matuszek M.A., Aristoteli L.P., Bannon P.G., et al. Haptoglobin elutes from human atherosclerotic coronary arteries-a potential marker of arterial pathology. Atherosclerosis 2003, 168:389-396.
36. Asleh R., Levy A.P. Invivo and invitro studies establishing haptoglobin as a major susceptibility gene for diabetic vascular disease. Vasc Health Risk Management 2005, 1:19-28.
37. Levy A.P., Hochberg I., Jablonski K., et al. Haptoglobin phenotype is an independent risk factor for cardiovascular disease in individuals with diabetes: the strong heart study. JAm Coll Cardiol 2002, 40:1984-1990.
38. Srivastava R.A., Jahagirdar R., Azhar S., Sharma S., Bisgaier C.L. Peroxisome proliferator-activated receptor-alpha selective ligand reduces adiposity, improves insulin sensitivity and inhibits atherosclerosis in LDL receptor-deficient mice. Mol Cell Biochem 2006, 285:35-50.
39. Srivastava R.A. Evaluation of anti-atherosclerotic activities of PPAR-alpha, PPAR-gamma, and LXR agonists in hyperlipidemic atherosclerosis-susceptible F(1)B hamsters. Atherosclerosis 2011, 214:86-93.
40. Rekhter M., Staschke K., Estridge T., et al. Genetic ablation of IRAK4 kinase activity inhibits vascular lesion formation. Biochem Biophys Res Commun 2008, 367:642-648.
41. Tangirala R.K., Tsukamoto K., Chun S.H., Usher D., Pure E., Rader D.J. Regression of atherosclerosis induced by liver-directed gene transfer of apolipoprotein A-I in mice. Circulation 1999, 100:1816-1822.
42. Li R.J., Yang Y., Wang Y.H., et al. Micro-ultrasonographic imaging of atherosclerotic progression and correlation with inflammatory markers in apolipoprotein-E knockout mice. Texas heart institute journal/from the texas heart institute of st luke's episcopal hospital. Tex Children's Hosp 2011, 38:364-370.
43. Cheng C., Tempel D., Den Dekker W.K., et al. Ets2 determines the inflammatory state of endothelial cells in advanced atherosclerotic lesions. Circ Res 2011, 109:382-395.
44. Liu X., Zhao G., Yan Y., Bao L., Chen B., Qi R. Ginkgolide B reduces atherogenesis and vascular inflammation in ApoE(-/-) mice. PLoS One 2012, 7. e36237.
45. Trogan E., Feig J.E., Dogan S., et al. Gene expression changes in foam cells and the role of chemokine receptor CCR7 during atherosclerosis regression in ApoE-deficient mice. Proc Natl Acad Sci U S A 2006, 103:3781-3786.
46. Davignon J. Apolipoprotein E and atherosclerosis: beyond lipid effect. Arterioscler Thromb Vasc Biol 2005, 25:267-269.
47. Raffai R.L., Loeb S.M., Weisgraber K.H. Apolipoprotein E promotes the regression of atherosclerosis independently of lowering plasma cholesterol levels. Arterioscler Thromb Vasc Biol 2005, 25:436-441.
48. Shimomura I., Bashmakov Y., Shimano H., Horton J.D., Goldstein J.L., Brown M.S. Cholesterol feeding reduces nuclear forms of sterol regulatory element binding proteins in hamster liver. Proc Natl Acad Sci U S A 1997, 94:12354-12359.
49. Srivastava R.A., Ito H., Hess M., Srivastava N., Schonfeld G. Regulation of low density lipoprotein receptor gene expression in HepG2 and Caco2 cells by palmitate, oleate, and 25-hydroxycholesterol. JLipid Res 1995, 36:1434-1446.
50. Fu X., Menke J.G., Chen Y., et al. 27-hydroxycholesterol is an endogenous ligand for liver X receptor in cholesterol-loaded cells. JBiol Chem 2001, 276:38378-38387.
51. Navab M., Anantharamaiah G.M., Reddy S.T., et al. Oral D-4F causes formation of pre-beta high-density lipoprotein and improves high-density lipoprotein-mediated cholesterol efflux and reverse cholesterol transport from macrophages in apolipoprotein E-null mice. Circulation 2004, 109:3215-3220.
52. Gaudreault N., Kumar N., Posada J.M., et al. ApoE suppresses atherosclerosis by reducing lipid accumulation in circulating monocytes and the expression of inflammatory molecules on monocytes and vascular endothelium. Arterioscler Thromb Vasc Biol 2012, 32:264-272.
53. Boden W.E., Probstfield J.L., Anderson T., et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. NEngl J Med 2011, 365:2255-2267.
54. Tonkin A., Hunt D., Voysey M., et al. Effects of fenofibrate on cardiovascular events in patients with diabetes, with and without prior cardiovascular disease: the fenofibrate intervention and event lowering in diabetes (FIELD) study. Am Heart J 2012, 163:508-514.
55. Dunbar R., Cuchel M., Millar J.S., Schwartz C.C., Raper A.C., Ochotny R., et al. Niacin Does not accelerate reverse cholesterol transport in Man. ATVB Sci Sess 2013.
56. Barter P.J., Caulfield M., Eriksson M., et al. Effects of torcetrapib in patients at high risk for coronary events. NEngl J Med 2007, 357(21):2109-2122.
57. Schwartz G.G., Olsson A.G., Abt M., et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. NEngl J Med 2012, 367:2089-2099.
58. Huang Y., Didonato J.A., Levison B.S., et al. An abundant dysfunctional apolipoprotein A1 in human atheroma. Nat Med 2014, 20:193-203.
59. de la Llera Moya M., McGillicuddy F.C., Hinkle C.C., et al. Inflammation modulates human HDL composition and function invivo. Atherosclerosis 2012.
60. Barter P.J., Puranik R., Rye K.A. New insights into the role of HDL as an anti-inflammatory agent in the prevention of cardiovascular disease. Curr Cardiol Rep 2007, 9(6):493-498.
61. McGillicuddy F.C., de la Llera Moya M., Hinkle C.C., et al. Inflammation impairs reverse cholesterol transport invivo. Circulation 2009, 119:1135-1145.
62. Majdalawieh A., Ro H.S. LPS-induced suppression of macrophage cholesterol efflux is mediated by adipocyte enhancer-binding protein 1. Int J Biochem Cell Biol 2009, 41:1518-1525.
63. Pajkrt D., Doran J.E., Koster F., et al. Antiinflammatory effects of reconstituted high-density lipoprotein during human endotoxemia. JExp Med 1996, 184:1601-1608.
64. Yvan-Charvet L., Kling J., Pagler T., et al. Cholesterol efflux potential and antiinflammatory properties of high-density lipoprotein after treatment with niacin or anacetrapib. Arterioscler Thromb Vasc Biol 2010, 30:1430-1438.
65. Moore R.E., Navab M., Millar J.S., et al. Increased atherosclerosis in mice lacking apolipoprotein A-I attributable to both impaired reverse cholesterol transport and increased inflammation. Circ Res 2005, 97:763-771.
66. Libby P. Inflammation and cardiovascular disease mechanisms. Am J Clin Nutr 2006, 83:456S-460S.
67. Libby P. Inflammation in atherosclerosis. Nature 2002, 420:868-874.
68. Libby P., Crea F. Clinical implications of inflammation for cardiovascular primary prevention. Eur Heart J 2010, 31:777-783.
69. Rader D.J., Daugherty A. Translating molecular discoveries into new therapies for atherosclerosis. Nature 2008, 451:904-913.
70. Cybulsky M.I., Gimbrone M.A. Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis. Science 1991, 251:788-791.
71. Li H., Cybulsky M.I., Gimbrone M.A., Libby P. Inducible expression of vascular cell adhesion molecule-1 by vascular smooth muscle cells invitro and within rabbit atheroma. Am J Pathol 1993, 143:1551-1559.
72. Gu L., Okada Y., Clinton S.K., et al. Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. Mol Cell 1998, 2:275-281.
73. Boring L., Gosling J., Cleary M., Charo I.F. Decreased lesion formation in CCR2-/- mice reveals a role for chemokines in the initiation of atherosclerosis. Nature 1998, 394:894-897.
74. Libby P., Ridker P.M. Inflammation and atherosclerosis: role of C-reactive protein in risk assessment. Am J Med 2004, 116(Suppl.6A):9S-16S.
75. Ridker P.M., Silvertown J.D. Inflammation, C-reactive protein, and atherothrombosis. JPeriodontol 2008, 79:1544-1551.
76. Ridker P.M., Hennekens C.H., Buring J.E., Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. NEngl J Med 2000, 342:836-843.
77. Lemieux I., Pascot A., Prud'homme D., et al. Elevated C-reactive protein: another component of the atherothrombotic profile of abdominal obesity. Arterioscler Thromb Vasc Biol 2001, 21:961-967.
78. Saito M., Ishimitsu T., Minami J., Ono H., Ohrui M., Matsuoka H. Relations of plasma high-sensitivity C-reactive protein to traditional cardiovascular risk factors. Atherosclerosis 2003, 167:73-79.
79. Ridker P.M., Rifai N., Clearfield M., et al. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. NEngl J Med 2001, 344:1959-1965.
80. Ridker P.M., Danielson E., Fonseca F.A., et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. NEngl J Med 2008, 359:2195-2207.
81. Gijbels M.J., van der Cammen M., van der Laan L.J., et al. Progression and regression of atherosclerosis in APOE3-Leiden transgenic mice: an immunohistochemical study. Atherosclerosis 1999, 143:15-25.
82. Dobryszycka W. Biological functions of haptoglobin-new pieces to an old puzzle. Eur J Clin Chem Clin Biochem 1997, 35:647-654.
83. Engstrom G., Hedblad B., Tyden P., Lindgarde F. Inflammation-sensitive plasma proteins are associated with increased incidence of heart failure: a population-based cohort study. Atherosclerosis 2009, 202:617-622.
84. Asleh R., Miller-Lotan R., Aviram M., et al. Haptoglobin genotype is a regulator of reverse cholesterol transport in diabetes invitro and invivo. Circ Res 2006, 99:1419-1425.
85. Schwartz A., Blum S., Asleh R., Pollak M., Kalet-Litman S., Levy A.P. Pharmacogenomic application of the haptoglobin genotype in the treatment of HDL dysfunction. Pharmacogenomics Pers Med 2009, 2:1-8.
86. Kalmovarin N., Friedrichs W.E., O'Brien H.V., Linehan L.A., Bowman B.H., Yang F. Extrahepatic expression of plasma protein genes during inflammation. Inflammation 1991, 15:369-379.
87. Ross R. Atherosclerosis is an inflammatory disease. Am Heart J 1999, 138:S419-S420.
88. Graversen J.H., Madsen M., Moestrup S.K. CD163: a signal receptor scavenging haptoglobin-hemoglobin complexes from plasma. Int J Biochem Cell Biol 2002, 34:309-314.
89. Kaempfer T., Duerst E., Gehrig P., et al. Extracellular hemoglobin polarizes the macrophage proteome toward Hb-clearance, enhanced antioxidant capacity and suppressed HLA class 2 expression. JProteome Res 2011, 10:2397-2408.
90. Buechler C., Ritter M., Orso E., Langmann T., Klucken J., Schmitz G. Regulation of scavenger receptor CD163 expression in human monocytes and macrophages by pro- and antiinflammatory stimuli. JLeukoc Biol 2000, 67:97-103.
91. Kristiansen M., Graversen J.H., Jacobsen C., et al. Identification of the haemoglobin scavenger receptor. Nature 2001, 409:198-201.
92. Wallberg-Jonsson S., Cvetkovic J.T., Sundqvist K.G., Lefvert A.K., Rantapaa-Dahlqvist S. Activation of the immune system and inflammatory activity in relation to markers of atherothrombotic disease and atherosclerosis in rheumatoid arthritis. JRheumatol 2002, 29:875-882.
93. Morita T. Heme oxygenase and atherosclerosis. Arterioscler Thromb Vasc Biol 2005, 25:1786-1795.
94. Smeets M.B., Pasterkamp G., Lim S.K., Velema E., van Middelaar B., de Kleijn D.P. Nitric oxide synthesis is involved in arterial haptoglobin expression after sustained flow changes. FEBS Lett 2002, 529:221-224.
95. Belkina A.C., Nikolajczyk B.S., Denis G.V. BET protein function is required for inflammation: Brd2 genetic disruption and BET inhibitor JQ1 impair mouse macrophage inflammatory responses. JImmunol 2013, 190:3670-3678.
96. Rekhter M., Chandrasekhar K., Gifford-Moore D., et al. Immunohistochemical analysis of target proteins of Rho-kinase in a mouse model of accelerated atherosclerosis. Exp Clin Cardiol 2007, 12:169-174.
97. Srivastava R.A.K., Dalal R., Lobo A., Parikh S., Sharma S. Anovel anti-inflammatory Natural product and its active ingredient, 7-hydroxy frullanolide inhibits expression of vcam1 and icam1, and slows progression of athersoclerosis 2009, International Atherosclerosis Society Meeting, Boston.