Skip to main content
SpringerLink
Log in

Negatively charged low-density lipoprotein is associated with atherogenic risk in hypertensive patients

  • Original Article
  • Published:
Heart and Vessels Aims and scope Submit manuscript

Abstract

Negatively charged low-density lipoprotein (LDL), generated via multiple processes such as oxidation, acetylation, or glycosylation, plays a key role in the initiation and progression of atherosclerosis and related diseases. Anion-exchange high-performance liquid chromatography (AE-HPLC) can subfractionate LDL into LDL-1, LDL-2, and LDL-3 based on LDL particle charge, but the clinical significance of LDL subfractions has not yet been elucidated. The aim of this study was to determine the clinical significance of these fractions with particular regard to atherogenic risk in hypertensive patients. Ninety-eight patients with essential hypertension (age 67.0 ± 10.7 years; 54 males) were enrolled in the present study. The relationships between LDL subfractions and atherogenic risk factors, including lipid profiles, blood pressure and plasma 8-isoprostane as a marker of oxidative stress, were examined. LDL-1 levels were significantly and negatively correlated with body mass index (r = −0.384, p < 0.001), systolic blood pressure (r = −0.457, p < 0.001), non-high-density lipoprotein cholesterol levels (r = −0.457, p < 0.001) and 8-isoprostane levels (r = −0.415, p < 0.001). LDL-3, which is the most negatively charged fraction of total LDL, was significantly and positively correlated with these parameters (r = 0.267, 0.481, 0.357, and 0.337, respectively). LDL-1 levels were significantly lower (p < 0.001), and LDL-2 and LDL-3 levels were significantly higher (each p < 0.001) in patients with poorly controlled hypertension than in patients with well-controlled hypertension. In addition, an increase in the total number of traditional risk factors at time of study participation, but not previous diagnosis, was associated with a decrease in LDL-1 levels and increases in LDL-2 and LDL-3 levels. These data suggest that LDL subfractions are associated with multiple atherogenic risk factors and that treatment to modify these risk factors could result in changes in LDL subfraction levels. In conclusion, LDL subfractions isolated by AE-HPLC may represent a marker of atherogenic risk in patients with hypertension.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Steinberg D (1997) Low-density lipoprotein oxidation and its pathobiological significance. J Biol Chem 272:20963–20966

    Article  PubMed  CAS  Google Scholar 

  2. Berliner JA, Navab M, Fogelman AM, Frank JS, Demer LL, Edwards PA, Watson AD, Lusis AJ (1995) Atherosclerosis: basic mechanisms. Oxidation, inflammation, and genetics. Circulation 91:2488–2496

    Article  PubMed  CAS  Google Scholar 

  3. Rizzo M, Berneis K (2007) Who needs to care about small, dense low-density lipoproteins? Int J Clin Pract 61:1949–1956

    Article  PubMed  CAS  Google Scholar 

  4. Tavridou A, Efthimiadis A, Efthimiadis I, Manolopoulos VG (2010) Simvastatin-induced changes in circulating oxidized low-density lipoprotein in different types of dyslipidemia. Heart Vessels 25:288–293

    Article  PubMed  Google Scholar 

  5. Dong K, Ge JH, Gu SL, Li S, Zhu WG, Fan FY, Zhu JH (2011) Ox-LDL can enhance the interaction of mice natural killer cells and dendritic cells via the CD48-2B4 pathway. Heart Vessels. doi:1007/s00380-010-0102-4

    PubMed  Google Scholar 

  6. Packard CJ (2006) Small dense low-density lipoprotein and its role as an independent predictor of cardiovascular disease. Curr Opin Lipidol 17:412–417

    Article  PubMed  CAS  Google Scholar 

  7. Berneis KK, Krauss RM (2002) Metabolic origins and clinical significance of LDL heterogeneity. J Lipid Res 43:1363–1379

    Article  PubMed  CAS  Google Scholar 

  8. La Belle M, Blanche PJ, Krauss RM (1997) Charge properties of low-density lipoprotein subclasses. J Lipid Res 38:690–700

    PubMed  CAS  Google Scholar 

  9. Sanchez-Quesada JL, Benitez S, Ordonez-Llanos J (2004) Electronegative low-density lipoprotein. Curr Opin Lipidol 15:329–335

    Article  PubMed  CAS  Google Scholar 

  10. Sevanian A, Bittolo-Bon G, Cazzolato G, Hodis H, Hwang J, Zamburlini A, Maiorino M, Ursini F (1997) LDL- is a lipid hydroperoxide-enriched circulating lipoprotein. J Lipid Res 38:419–428

    PubMed  CAS  Google Scholar 

  11. Sevanian A, Hwang J, Hodis H, Cazzolato G, Avogaro P, Bittolo-Bon G (1996) Contribution of an in vivo oxidized LDL to LDL oxidation and its association with dense LDL subpopulations. Arterioscler Thromb Vasc Biol 16:784–793

    Article  PubMed  CAS  Google Scholar 

  12. Hodis HN, Kramsch DM, Avogaro P, Bittolo-Bon G, Cazzolato G, Hwang J, Peterson H, Sevanian A (1994) Biochemical and cytotoxic characteristics of an in vivo circulating oxidized low-density lipoprotein (LDL-). J Lipid Res 35:669–677

    PubMed  CAS  Google Scholar 

  13. Cazzolato G, Avogaro P, Bittolo-Bon G (1991) Characterization of a more electronegatively charged LDL subfraction by ion exchange HPLC. Free Radic Biol Med 11:247–253

    Article  PubMed  CAS  Google Scholar 

  14. Avogaro P, Bon GB, Cazzolato G (1988) Presence of a modified low-density lipoprotein in humans. Arteriosclerosis 8:79–87

    Article  PubMed  CAS  Google Scholar 

  15. Sanchez-Quesada JL, Camacho M, Anton R, Benitez S, Vila L, Ordonez-Llanos J (2003) Electronegative LDL of FH subjects: chemical characterization and induction of chemokine release from human endothelial cells. Atherosclerosis 166:261–270

    Article  PubMed  CAS  Google Scholar 

  16. Nishi K, Itabe H, Uno M, Kitazato KT, Horiguchi H, Shinno K, Nagahiro S (2002) Oxidized LDL in carotid plaques and plasma associates with plaque instability. Arterioscler Thromb Vasc Biol 22:1649–1654

    Article  PubMed  CAS  Google Scholar 

  17. Shimano H, Yamada N, Ishibashi S, Mokuno H, Mori N, Gotoda T, Harada K, Akanuma Y, Murase T, Yazaki Y, Takaku F (1991) Oxidation-labile subfraction of human plasma low-density lipoprotein isolated by ion-exchange chromatography. J Lipid Res 32:763–773

    PubMed  CAS  Google Scholar 

  18. Benitez S, Ordonez-Llanos J, Franco M, Marin C, Paz E, Lopez-Miranda J, Otal C, Perez-Jimenez F, Sanchez-Quesada JL (2004) Effect of simvastatin in familial hypercholesterolemia on the affinity of electronegative low-density lipoprotein subfractions to the low-density lipoprotein receptor. Am J Cardiol 93:414–420

    Article  PubMed  CAS  Google Scholar 

  19. Zhang B, Matsunaga A, Rainwater DL, Miura S, Noda K, Nishikawa H, Uehara Y, Shirai K, Ogawa M, Saku K (2009) Effects of rosuvastatin on electronegative LDL as characterized by capillary isotachophoresis: the ROSARY study. J Lipid Res 50:1832–1841

    Article  PubMed  CAS  Google Scholar 

  20. Vedie B, Jeunemaitre X, Megnien JL, Myara I, Trebeden H, Simon A, Moatti N (1998) Charge heterogeneity of LDL in asymptomatic hypercholesterolemic men is related to lipid parameters and variations in the ApoB and CIII genes. Arterioscler Thromb Vasc Biol 18:1780–1789

    Article  PubMed  CAS  Google Scholar 

  21. Bittolo-Bon G, Cazzolato G, Avogaro P (1994) Probucol protects low-density lipoproteins from in vitro and in vivo oxidation. Pharmacol Res 29:337–344

    Article  PubMed  CAS  Google Scholar 

  22. Sanchez-Quesada JL, Benitez S, Otal C, Franco M, Blanco-Vaca F, Ordonez-Llanos J (2002) Density distribution of electronegative LDL in normolipemic and hyperlipemic subjects. J Lipid Res 43:699–705

    PubMed  CAS  Google Scholar 

  23. Sanchez-Quesada JL, Perez A, Caixas A, Rigla M, Payes A, Benitez S, Ordonez-Llanos J (2001) Effect of glycemic optimization on electronegative low-density lipoprotein in diabetes: relation to nonenzymatic glycosylation and oxidative modification. J Clin Endocrinol Metab 86:3243–3249

    Article  PubMed  CAS  Google Scholar 

  24. Moro E, Alessandrini P, Zambon C, Pianetti S, Pais M, Cazzolato G, Bon GB (1999) Is glycation of low-density lipoproteins in patients with type 2 diabetes mellitus a LDL pre-oxidative condition? Diabet Med 16:663–669

    Article  PubMed  CAS  Google Scholar 

  25. Moro E, Zambon C, Pianetti S, Cazzolato G, Pais M, Bittolo Bon G (1998) Electronegative low-density lipoprotein subform (LDL-) is increased in type 2 (non-insulin-dependent) microalbuminuric diabetic patients and is closely associated with LDL susceptibility to oxidation. Acta Diabetol 35:161–164

    Article  PubMed  CAS  Google Scholar 

  26. Sanchez-Quesada JL, Perez A, Caixas A, Ordonmez-Llanos J, Carreras G, Payes A, Gonzalez-Sastre F, de Leiva A (1996) Electronegative low-density lipoprotein subform is increased in patients with short-duration IDDM and is closely related to glycaemic control. Diabetologia 39:1469–1476

    Article  PubMed  CAS  Google Scholar 

  27. Ziouzenkova O, Asatryan L, Akmal M, Tetta C, Wratten ML, Loseto-Wich G, Jurgens G, Heinecke J, Sevanian A (1999) Oxidative cross-linking of ApoB100 and hemoglobin results in low-density lipoprotein modification in blood. Relevance to atherogenesis caused by hemodialysis. J Biol Chem 274:18916–18924

    Article  PubMed  CAS  Google Scholar 

  28. De Castellarnau C, Sanchez-Quesada JL, Benitez S, Rosa R, Caveda L, Vila L, Ordonez-Llanos J (2000) Electronegative LDL from normolipemic subjects induces IL-8 and monocyte chemotactic protein secretion by human endothelial cells. Arterioscler Thromb Vasc Biol 20:2281–2287

    Article  PubMed  Google Scholar 

  29. Zhang B, Kaneshi T, Ohta T, Saku K (2005) Relation between insulin resistance and fast-migrating LDL subfraction as characterized by capillary isotachophoresis. J Lipid Res 46:2265–2277

    Article  PubMed  CAS  Google Scholar 

  30. Schmitz G, Mollers C, Richter V (1997) Analytical capillary isotachophoresis of human serum lipoproteins. Electrophoresis 18:1807–1813

    Article  PubMed  CAS  Google Scholar 

  31. Kitano S, Yoshida Y, Kawano K, Hibi N, Niki E (2007) Oxidative status of human low-density lipoprotein isolated by anion-exchange high-performance liquid chromatography—assessment by total hydroxyoctadecadienoic acid, 7-hydroxycholesterol, and 8-iso-prostaglandin F(2alpha). Anal Chim Acta 585:86–93

    Article  PubMed  CAS  Google Scholar 

  32. Yamaguchi Y, Kagota S, Kunitomo M, Haginaka J (1998) Evidence of modified lipoprotein in the plasma of Watanabe heritable hyperlipidemic rabbits by anion-exchange high-performance liquid chromatographic assay. Atherosclerosis 139:323–331

    Article  PubMed  CAS  Google Scholar 

  33. Bittolo-Bon G, Cazzolato G (1999) Analytical capillary isotachophoresis of total plasma lipoproteins: a new tool to identify atherogenic low-density lipoproteins. J Lipid Res 40:170–177

    PubMed  CAS  Google Scholar 

  34. de Queiroz Mello AP, da Silva IT, Oliveira AS, Nunes VS, Abdalla DS, Gidlund M, Damasceno NR (2010) Electronegative low-density lipoprotein is associated with dense low-density lipoprotein in subjects with different levels of cardiovascular risk. Lipids 45:619–625

    Article  PubMed  CAS  Google Scholar 

  35. Noda K, Zhang B, Uehara Y, Miura S, Matsunaga A, Saku K (2005) Potent capillary isotachophoresis (cITP) for analyzing a marker of coronary heart disease risk and electronegative low-density lipoprotein (LDL) in small dense LDL fraction. Circ J 69:1568–1570

    Article  PubMed  Google Scholar 

  36. Lu J, Yang JH, Burns AR, Chen HH, Tang D, Walterscheid JP, Suzuki S, Yang CY, Sawamura T, Chen CH (2009) Mediation of electronegative low-density lipoprotein signaling by LOX-1: a possible mechanism of endothelial apoptosis. Circ Res 104:619–627

    Article  PubMed  CAS  Google Scholar 

  37. Kato T, Inoue T, Yamagishi S, Morooka T, Okimoto T, Node K (2006) Low-density lipoprotein subfractions and the prevalence of silent lacunar infarction in subjects with essential hypertension. Hypertens Res 29:303–307

    Article  PubMed  Google Scholar 

  38. Yamaguchi Y, Matsuno S, Kagota S, Haginaka J, Kunitomo M (2004) Peroxynitrite-mediated oxidative modification of low-density lipoprotein by aqueous extracts of cigarette smoke and the preventive effect of fluvastatin. Atherosclerosis 172:259–265

    Article  PubMed  CAS  Google Scholar 

  39. Yamaguchi Y, Matsuno S, Kagota S, Haginaka J, Kunitomo M (2001) Oxidants in cigarette smoke extract modify low-density lipoprotein in the plasma and facilitate atherogenesis in the aorta of Watanabe heritable hyperlipidemic rabbits. Atherosclerosis 156:109–117

    Article  PubMed  CAS  Google Scholar 

  40. Yamaguchi Y, Kagota S, Haginaka J, Kunitomo M (2000) Evidence of modified LDL in the plasma of hypercholesterolemic WHHL rabbits injected with aqueous extracts of cigarette smoke. Environ Toxicol Pharmacol 8:255–260

    Article  PubMed  CAS  Google Scholar 

  41. Inoue N, Kawashima S, Hirata KI, Rikitake Y, Takeshita S, Yamochi W, Akita H, Yokoyama M (1998) Stretch force on vascular smooth muscle cells enhances oxidation of LDL via superoxide production. Am J Physiol 274:H1928–H1932

    PubMed  CAS  Google Scholar 

  42. Hishikawa K, Luscher TF (1997) Pulsatile stretch stimulates superoxide production in human aortic endothelial cells. Circulation 96:3610–3616

    Article  PubMed  CAS  Google Scholar 

  43. Griendling KK, Sorescu D, Ushio-Fukai M (2000) NAD(P)H oxidase: role in cardiovascular biology and disease. Circ Res 86:494–501

    Article  PubMed  CAS  Google Scholar 

  44. Nakazono K, Watanabe N, Matsuno K, Sasaki J, Sato T, Inoue M (1991) Does superoxide underlie the pathogenesis of hypertension? Proc Natl Acad Sci USA 88:10045–10048

    Article  PubMed  CAS  Google Scholar 

  45. Torres JL, Ridker PM (2003) Clinical use of high sensitivity C-reactive protein for the prediction of adverse cardiovascular events. Curr Opin Cardiol 18:471–478

    Article  PubMed  Google Scholar 

  46. Ridker PM (2001) High-sensitivity C-reactive protein: potential adjunct for global risk assessment in the primary prevention of cardiovascular disease. Circulation 103:1813–1818

    Article  PubMed  CAS  Google Scholar 

  47. Shoji T, Hatsuda S, Tsuchikura S, Shinohara K, Kimoto E, Koyama H, Emoto M, Nishizawa Y (2009) Small dense low-density lipoprotein cholesterol concentration and carotid atherosclerosis. Atherosclerosis 202:582–588

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was partly supported by JSPS Grant-in-Aid for Scientific Research (C) (21590902) (to S.I.).

Author information

Authors and Affiliations

  1. Department of Cardiovascular Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan

    Jungo Urata, Satoshi Ikeda, Seiji Koga, Tomoo Nakata, Tomohiko Yasunaga, Koichiro Sonoda, Yuji Koide, Naoto Ashizawa & Koji Maemura

  2. Second Department of Internal Medicine, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan

    Shigeru Kohno

Authors
  1. Jungo Urata
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Satoshi Ikeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Seiji Koga
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tomoo Nakata
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tomohiko Yasunaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Koichiro Sonoda
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yuji Koide
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Naoto Ashizawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Shigeru Kohno
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Koji Maemura
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Satoshi Ikeda.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Urata, J., Ikeda, S., Koga, S. et al. Negatively charged low-density lipoprotein is associated with atherogenic risk in hypertensive patients. Heart Vessels 27, 235–242 (2012). https://doi.org/10.1007/s00380-011-0139-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00380-011-0139-z

Keywords

Search

Navigation