Atherosclerosis
Volume 210, Issue 2 , Pages 381-387 , June 2010

Ritonavir protects against the development of atherosclerosis in APOE*3-Leiden mice

  • Marion A.M. den Boer

      Affiliations

    • Dept. of General Internal Medicine, Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, Netherlands
  • ,
  • Marit Westerterp

      Affiliations

    • Dept. of General Internal Medicine, Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, Netherlands
  • ,
  • Jitske de Vries-van der Weij

      Affiliations

    • Dept. of Human Genetics, Leiden University Medical Center, Leiden, Netherlands
    • Netherlands Organization for Applied Scientific Research-Quality of Life, Leiden, Netherlands
  • ,
  • Yanan Wang

      Affiliations

    • Dept. of General Internal Medicine, Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, Netherlands
  • ,
  • Lihui Hu

      Affiliations

    • Dept. of General Internal Medicine, Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, Netherlands
  • ,
  • Sonia M.S. Espirito Santo

      Affiliations

    • Dept. of General Internal Medicine, Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, Netherlands
  • ,
  • Teake Kooistra

      Affiliations

    • Netherlands Organization for Applied Scientific Research-Quality of Life, Leiden, Netherlands
  • ,
  • Peter Reiss

      Affiliations

    • Dept. of Infectious Diseases, Tropical Medicine and AIDS, Academic Medical Center, Amsterdam, Netherlands
  • ,
  • Johannes A. Romijn

      Affiliations

    • Dept. of General Internal Medicine, Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, Netherlands
  • ,
  • Louis M. Havekes

      Affiliations

    • Dept. of General Internal Medicine, Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, Netherlands
    • Dept. of Cardiology, Leiden University Medical Center, Leiden, Netherlands
    • Netherlands Organization for Applied Scientific Research-Quality of Life, Leiden, Netherlands
  • ,
  • Patrick C.N. Rensen

      Affiliations

    • Dept. of General Internal Medicine, Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, Netherlands
    • Netherlands Organization for Applied Scientific Research-Quality of Life, Leiden, Netherlands
    • Corresponding Author InformationCorresponding author at: Leiden University Medical Center, Dept. of Endocrinology and Metabolic Diseases, Room C4-R81, P.O. Box 9600, 2300 RC Leiden, Netherlands. Tel.: +31 71 526 1830; fax: +31 71 524 8136.

Received 18 March 2009 ,Revised 5 November 2009 ,Accepted 5 November 2009.

References 

  1. Carr A, Samaras K, Chisholm DJ, Cooper DA. Pathogenesis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance. Lancet. 1998;351:1881–1883
  2. Carr A, Samaras K, Burton S, et al. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS. 1998;12:F51–F58
  3. Chironi G, Escaut L, Gariepy J, et al. Brief report: carotid intima-media thickness in heavily pretreated HIV-infected patients. J Acquir Immune Defic Syndr. 2003;32:490–493
  4. Depairon M, Chessex S, Sudre P, et al. Premature atherosclerosis in HIV-infected individuals—focus on protease inhibitor therapy. AIDS. 2001;15:329–334
  5. Jerico C, Knobel H, Calvo N, et al. Subclinical carotid atherosclerosis in HIV-infected patients: role of combination antiretroviral therapy. Stroke. 2006;37:812–817
  6. Mercie P, Thiebaut R, Lavignolle V, et al. Evaluation of cardiovascular risk factors in HIV-1 infected patients using carotid intima-media thickness measurement. Ann Med. 2002;34:55–63
  7. de Saint ML, Vandhuick O, Guillo P, et al. Premature atherosclerosis in HIV positive patients and cumulated time of exposure to antiretroviral therapy (SHIVA study). Atherosclerosis. 2006;185:361–367
  8. Currier JS, Kendall MA, Zackin R, et al. Carotid artery intima-media thickness and HIV infection: traditional risk factors overshadow impact of protease inhibitor exposure. AIDS. 2005;19:927–933
  9. Sankatsing RR, Wit FW, Vogel M, et al. Increased carotid intima-media thickness in HIV patients treated with protease inhibitors as compared to non-nucleoside reverse transcriptase inhibitors. Atherosclerosis. 2009;202:589–595
  10. Friis-Moller N, Sabin CA, Weber R, et al. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med. 2003;349:1993–2003
  11. Friis-Moller N, Reiss P, Sabin CA, et al. Class of antiretroviral drugs and the risk of myocardial infarction. N Engl J Med. 2007;356:1723–1735
  12. Dressman J, Kincer J, Matveev SV, et al. HIV protease inhibitors promote atherosclerotic lesion formation independent of dyslipidemia by increasing CD36-dependent cholesteryl ester accumulation in macrophages. J Clin Invest. 2003;111:389–397
  13. Allred KF, Smart EJ, Wilson ME. Estrogen receptor-alpha mediates gender differences in atherosclerosis induced by HIV protease inhibitors. J Biol Chem. 2006;281:1419–1425
  14. VanderLaan PA, Reardon CA, Getz GS. Site specificity of atherosclerosis: site-selective responses to atherosclerotic modulators. Arterioscler Thromb Vasc Biol. 2004;24:12–22
  15. Zadelaar S, Kleemann R, Verschuren L, et al. Mouse models for atherosclerosis and pharmaceutical modifiers. Arterioscler Thromb Vasc Biol. 2007;27:1706–1721
  16. van Vlijmen BJ, van den Maagdenberg AM, Gijbels MJ, et al. Diet-induced hyperlipoproteinemia and atherosclerosis in apolipoprotein E3-Leiden transgenic mice. J Clin Invest. 1994;93:1403–1410
  17. Huisman MT, Smit JW, Wiltshire HR, Beijnen JH, Schinkel AH. Assessing safety and efficacy of directed P-glycoprotein inhibition to improve the pharmacokinetic properties of saquinavir coadministered with ritonavir. J Pharmacol Exp Ther. 2003;304:596–602
  18. Limoges J, Poluektova L, Ratanasuwan W, et al. The efficacy of potent anti-retroviral drug combinations tested in a murine model of HIV-1 encephalitis. Virology. 2001;281:21–34
  19. den Boer MA, Berbee JF, Reiss P, et al. Ritonavir impairs lipoprotein lipase-mediated lipolysis and decreases uptake of fatty acids in adipose tissue. Arterioscler Thromb Vasc Biol. 2006;26:124–129
  20. Shafran SD, Mashinter LD, Roberts SE. The effect of low-dose ritonavir monotherapy on fasting serum lipid concentrations. HIV Med. 2005;6:421–425
  21. Zambon A, Hashimoto SI, Brunzell JD. Analysis of techniques to obtain plasma for measurement of levels of free fatty acids. J Lipid Res. 1993;34:1021–1028
  22. Kleemann R, Princen HM, Emeis JJ, et al. Rosuvastatin reduces atherosclerosis development beyond and independent of its plasma cholesterol-lowering effect in APOE*3-Leiden transgenic mice: evidence for antiinflammatory effects of rosuvastatin. Circulation. 2003;108:1368–1374
  23. Stary HC, Chandler AB, Dinsmore RE, et al. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation. 1995;92:1355–1374
  24. Gijbels MJ, van der CM, van der Laan LJ, et al. Progression and regression of atherosclerosis in APOE3-Leiden transgenic mice: an immunohistochemical study. Atherosclerosis. 1999;143:15–25
  25. De Rijke YB, Biessen EA, Vogelezang CJ, van Berkel TJ. Binding characteristics of scavenger receptors on liver endothelial and Kupffer cells for modified low-density lipoproteins. Biochem J. 1994;304(Pt 1):69–73
  26. Rensen PC, Herijgers N, Netscher MH, et al. Particle size determines the specificity of apolipoprotein E-containing triglyceride-rich emulsions for the LDL receptor versus hepatic remnant receptor in vivo. J Lipid Res. 1997;38:1070–1084
  27. Purnell JQ, Zambon A, Knopp RH, et al. Effect of ritonavir on lipids and post-heparin lipase activities in normal subjects. AIDS. 2000;14:51–57
  28. Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA. 2007;298:299–308
  29. Serghides L, Nathoo S, Walmsley S, Kain KC. CD36 deficiency induced by antiretroviral therapy. AIDS. 2002;16:353–358
  30. Chawla A, Boisvert WA, Lee CH, et al. A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Mol Cell. 2001;7:161–171
  31. 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
  32. Li AC, Binder CJ, Gutierrez A, et al. Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARalpha, beta/delta, and gamma. J Clin Invest. 2004;114:1564–1576
  33. Tontonoz P, Nagy L, Alvarez JG, Thomazy VA, Evans RM. PPARgamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell. 1998;93:241–252
  34. van Eck M, Zimmermann R, Groot PH, Zechner R, van Berkel TJ. Role of macrophage-derived lipoprotein lipase in lipoprotein metabolism and atherosclerosis. Arterioscler Thromb Vasc Biol. 2000;20:E53–E62
  35. Kraus M, Malenke E, Gogel J, et al. Ritonavir induces endoplasmic reticulum stress and sensitizes sarcoma cells toward bortezomib-induced apoptosis. Mol Cancer Ther. 2008;7:1940–1948
  36. Wu X, Sun L, Zha W, et al. HIV protease inhibitors induce ER stress and disrupt barrier integrity in intestinal epithelial cells. Gastroenterology; in press.
  37. Kooistra T, Verschuren L, de Vries-Van der Weij J, et al. Fenofibrate reduces atherogenesis in ApoE*3Leiden mice: evidence for multiple antiatherogenic effects besides lowering plasma cholesterol. Arterioscler Thromb Vasc Biol. 2006;26:2322–2330
  38. Verschuren L, de Vries-Van der Weij J, Zadelaar S, Kleemann R, Kooistra T. LXR agonist suppresses atherosclerotic lesion growth and promotes lesion regression in ApoE*3Leiden mice: time course and mechanisms. J Lipid Res. 2009;50:301–311
  39. Foger B, Chase M, Amar MJ, et al. Cholesteryl ester transfer protein corrects dysfunctional high density lipoproteins and reduces aortic atherosclerosis in lecithin cholesterol acyltransferase transgenic mice. J Biol Chem. 1999;274:36912–36920
  40. van der Hoogt CC, de Haan W, Westerterp M, et al. Fenofibrate increases HDL-cholesterol by reducing cholesteryl ester transfer protein expression. J Lipid Res. 2007;48:1763–1771
  41. Tall A. Plasma lipid transfer proteins. Annu Rev Biochem. 1995;64:235–257

PII: S0021-9150(09)01000-4

doi: 10.1016/j.atherosclerosis.2009.11.043

Atherosclerosis
Volume 210, Issue 2 , Pages 381-387 , June 2010