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Deposition of Free Cholesterol in the Blood Vessels of Patients with Coronary Artery Disease: a Possible Novel Mechanism for Atherogenesis

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Lipids

Abstract

A cholesterol-rich nanoemulsion (LDE) that mimics the composition of low-density lipoprotein (LDL) acquires apoE in the plasma and is taken-up by the cells by LDL receptors. In this study, to verify whether free cholesterol (FC) and the cholesteryl ester (CE) components of LDL are taken-up differently by the vessels. LDE labeled with 3H-cholesterol and 14C-cholesteryl oleate was injected into 20 coronary artery disease patients 24 h before a scheduled myocardial coronary artery bypass grafting. The plasma kinetics of both radiolabels was determined from plasma samples collected over 24 h, and fragments of vessels discarded during surgery were collected and analyzed for radioactivity. LDE FC was removed faster than CE. The radioactive counting of LDE CE was greater than that of LDE FC in the blood, but the uptake of FC was markedly greater than that of CE in all fragments: fivefold greater in the aorta (p = 0.04), fourfold greater in the internal thoracic artery (p = 0.03), tenfold greater in the saphenous vein (p = 0.01) and threefold in the radial artery (p = 0.05). In conclusion, the greater removal from plasma of FC compared with CE and the remarkably greater vessel tissue uptake of FC compared with CE suggests that, in the plasma, FC dissociates from the nanoemulsion particles and precipitates in the vessels. Considering LDE as an artificial nanoemulsion model for LDL, our results suggest that dissociation of FC from lipoprotein particles and deposition in the vessel wall may play a role as an independent mechanism in atherogenesis.

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References

  1. Stein O, Stein Y (2005) Lipid transfer proteins (LTP) and atherosclerosis. Atherosclerosis 178:217–230

    Article  PubMed  CAS  Google Scholar 

  2. Dobiasova M, Frohlich J (1998) Understanding the mechanism of LCAT reaction may help to explain the high predictive value of LDL/HDL cholesterol ratio. Physiol Res 47:387–397

    PubMed  CAS  Google Scholar 

  3. Maranhão RC, Roland IA, Toffoletto O, Ramires JA, Goncalves RP, Mesquita CH, Pileggi F (1997) Plasma kinetic behavior in hyperlipidemic subjects of a lipidic microemulsion that binds to low density lipoprotein receptors. Lipids 32:627–633

    Article  PubMed  Google Scholar 

  4. Sposito AC, Lemos PA, Santos RD, Hueb W, Vinagre CG, Quintella E, Carneiro O, Chapman MJ, Ramires JA, Maranhão RC (2004) Impaired intravascular triglyceride lipolysis constitutes a marker of clinical outcome in patients with stable angina undergoing secondary prevention treatment: a long-term follow-up study. J Am Coll Cardiol 43:2225–2232

    Article  PubMed  CAS  Google Scholar 

  5. Puk CG, Vinagre CG, Bocchi E, Bacal F, Stolf N, Maranhão RC (2004) Plasma kinetics of a cholesterol-rich microemulsion in patients submitted to heart transplantation. Transplantation 78:1177–1181

    Article  PubMed  CAS  Google Scholar 

  6. Maranhão RC, Garicochea B, Silva EL, Dorlhiac-Llacer P, Cadena SM, Coelho IJ, Meneghetti JC, Pileggi FJ, Chamone DA (1994) Plasma kinetics and biodistribution of a lipid emulsion resembling low-density lipoprotein in patients with acute leukemia. Cancer Res 54:4660–4666

    PubMed  Google Scholar 

  7. Maranhão RC, Feres MC, Martins MT, Mesquita CH, Toffoletto O, Vinagre CG, Gianinni SD, Pileggi F (1996) Plasma kinetics of a chylomicron-like emulsion in patients with coronary artery disease. Atherosclerosis 126:15–25

    Article  PubMed  Google Scholar 

  8. Hirata RD, Hirata MH, Mesquita CH, Cesar TB, Maranhão RC (1999) Effects of apolipoprotein B-100 on the metabolism of a lipid microemulsion model in rats. Biochim Biophys Acta 1437:53–62

    PubMed  CAS  Google Scholar 

  9. Santos RD, Hueb W, Oliveira AA, Ramires JA, Maranhão RC (2003) Plasma kinetics of a cholesterol-rich emulsion in subjects with or without coronary artery disease. J Lipid Res 44:464–469

    Article  PubMed  CAS  Google Scholar 

  10. Friedewald WT, Levy RI, Fredrickison DS (1972) Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without the use of the preparative ultracentrifugue. Clin Chem 18:499–502

    PubMed  CAS  Google Scholar 

  11. Nishikawa O, Yokoyama S, Kurasawa T, Yamamoto A (1986) A method for direct incorporation of radiolabeled cholesteryl ester into human plasma low-density lipoproteins: preparation of tracer substrate for cholesteryl ester transfer reaction between lipoproteins. J Biochem 99:295–301

    PubMed  CAS  Google Scholar 

  12. Dobiásová M, Adler L, Ohta T, Frohlich J (2000) Effect of labeling of plasma lipoproteins with [3H]cholesterol on values of esterification rate of cholesterol in apolipoprotein B-depleted plasma. J Lipid Res 41:1356–1357

    PubMed  Google Scholar 

  13. Matthews CME (1957) The theory of tracer experiments with I labelled plasma proteins. Phys Med Biol 2:36–42

    Article  PubMed  CAS  Google Scholar 

  14. Marchese SRM, Mesquita CH, Cunha IL (1998) Anacomp program application to calculate 137C transfer rates in marine organisms and dose in man. J Radioanal Nucl Chem 232:233–236

    Article  Google Scholar 

  15. Sowby FS (1984) Radiation protection. In: Limits for intakes of radionuclides by workers. ICRP publication 30. Part I. Pergamon, Oxford

  16. Maranhao RC, Graziani SR, Yamaguchi N, Melo RF, Latrilha MC, Rodrigues DG, Couto RD, Schreier S, Buzaid CA (2002) Association of carmustine with a lipid emulsion: in vitro, in vivo and preliminary studies in cancer patients. Cancer Chemother Pharmacol 49:487–498

    Article  PubMed  CAS  Google Scholar 

  17. Schwartz CC, Van den Broek JM, Cooper PS (2004) Lipoprotein cholesteryl ester production, transfer, and output in vivo in humans. J Lipid Res 45:1594–1607

    Article  PubMed  CAS  Google Scholar 

  18. Liao JK (1998) Endothelium and acute coronary syndromes. Clin Chem 44:1799–1808

    PubMed  CAS  Google Scholar 

  19. Kataoka H, Kume N, Miyamoto S, Minami M, Moriwaki H, Murase T, Sawamura T, Masaki T, Hashimoto N, Kita T (1999) Expression of lectinlike oxidized low-density lipoprotein receptor-1 in human atherosclerotic lesions. Circulation 99:3110–3117

    PubMed  CAS  Google Scholar 

  20. Llorente-Cortés V, Martinez-Gonzalez J, Badimon L. (2000). LDL receptor-related protein mediates uptake of aggregated LDL in human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 20:1572–1579

    PubMed  Google Scholar 

  21. Ricciarelli R, Zingg J-M, Azzi A (2000) Vitamin E reduces the uptake of oxidized LDL by inhibiting CD 36 scavenger receptor expression in cultured aortic smooth muscle cells. Circulation 102:82–87

    PubMed  CAS  Google Scholar 

  22. Santos RD, Chacra AP, Morikawa A, Vinagre CG, Maranhão RC (2005) Plasma kinetics of free and esterified cholesterol in familial hypercholesterolemia: effects of simvastatin. Lipids 40:737–743

    Article  PubMed  CAS  Google Scholar 

  23. Libby P (1990) Inflammatory and immune mechanisms in atherogenesis. In: Leaf A, Weber P (eds) Atherosclerosis reviews. Raven Press, New York, pp 70–89

    Google Scholar 

  24. Lundberg BB, Suominen LA (1985) Physicochemical transfer of [3H]cholesterol from plasma lipoproteins to cultured human fibroblasts. Biochem J 228:219–225

    PubMed  CAS  Google Scholar 

  25. Ohmura H, Mokuno H, Sawano M, Hatsumi C, Mitsugi Y, Watanabe Y, Daida H, Yamaguchi H (2002) Lipid compositional differences of small, dense low-density lipoprotein particle influence its oxidative susceptibility: possible implication of increased risk of coronary artery disease in subjects with phenotype B. Metabolism 51:1081–1087

    Article  PubMed  CAS  Google Scholar 

  26. Dayton S (1959) Turnover of cholesterol in the artery walls of normal chickens. Circ Res 7:468

    PubMed  CAS  Google Scholar 

  27. Newman HAI, Mccandless EL, Zilversmit DB (1961) The synthesis of C14-lipids in rabbit atheromatous lesions. J Biol Chem 236:1264

    PubMed  CAS  Google Scholar 

  28. Smith EB, Slater PB (1973) Lipids and low density lipoproteins in intima in relation to its morphological characteristics. Ciba Found Symp 12:39–53

    Google Scholar 

  29. Stender S, Christensen S, Nyvad O (1978) Uptake of labelled free and esterified cholesterol from plasma by the aortic intima—media tissue measured in vivo in three animal species. Atherosclerosis 31: 279–293

    Article  PubMed  CAS  Google Scholar 

  30. Bondjers G, Bjorkerud S (1977) Arterial repair and atherosclerosis after mechanical injury. VI. Cholesterol elimination in vitro from experimental atherosclerotic lesions. Exp Mol Pathol 26:341–349

    Article  PubMed  CAS  Google Scholar 

  31. Day AJ, Wahlqvist ML, Campbell DJ (1970) Differential uptake of cholesterol and of different cholesterol esters by atherosclerotic intima in vivo and in vitro. Atherosclerosis 11:301–320

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was supported by Fundação do Amparo à Pesquisa do Estado de São Paulo (FAPESP) and The Zerbini Foundation, both in São Paulo, Brazil. Dr Maranhão has a research award from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brasilia, Brazil.

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Authors and Affiliations

  1. Lipid Metabolism Laboratory and the Surgical Division, The Heart Institute (INCOR) of the Medical School Hospital, University of São Paulo, Sao Paulo, Brazil

    Ricardo D. Couto, Luís A. O. Dallan, Luiz A. F. Lisboa, Carmen G. C. Vinagre & Raul C. Maranhão

  2. Faculty of Pharmaceutical Sciences, University of São Paulo, Sao Paulo, Brazil

    Ricardo D. Couto, Carlos H. Mesquita & Raul C. Maranhão

  3. Instituto do Coração (InCor) do Hospital das Clínicas da USP, Laboratório de Metabolismo de Lípides, Avenida Dr Enéas C. Aguiar 44, 1° Subsolo, CEP-05403-000, Sao Paulo-SP, Brazil

    Raul C. Maranhão

Authors
  1. Ricardo D. Couto
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  2. Luís A. O. Dallan
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  3. Luiz A. F. Lisboa
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  4. Carlos H. Mesquita
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  5. Carmen G. C. Vinagre
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  6. Raul C. Maranhão
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Correspondence to Raul C. Maranhão.

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Couto, R.D., Dallan, L.A.O., Lisboa, L.A.F. et al. Deposition of Free Cholesterol in the Blood Vessels of Patients with Coronary Artery Disease: a Possible Novel Mechanism for Atherogenesis. Lipids 42, 411–418 (2007). https://doi.org/10.1007/s11745-007-3041-9

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  • DOI: https://doi.org/10.1007/s11745-007-3041-9

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