Skip to main content

Advertisement

SpringerLink
Log in

3′-UTR OLR1/LOX-1 gene polymorphism and endothelial dysfunction: molecular and vascular data in never-treated hypertensive patients

  • IM - ORIGINAL
  • Published:
Internal and Emergency Medicine Aims and scope Submit manuscript

Abstract

Endothelial dysfunction represents an independent predictor for clinical events. Genetic background may promote deleterious alterations of endothelial physiology. The aim of the study was to investigate the relationship between the rs1050283 polymorphism in the 3′-UTR of OLR1/LOX-1 gene and endothelial dysfunction in 178 never-treated hypertensive patients and 36 healthy subjects. The rs1050283 C/T single nucleotide polymorphism was detected, by TaqMan allelic discrimination assay. The influence of polymorphism on gene transcription rate was tested in 12 heterozygous hypertensive patients, by using an allelic imbalance assay. Forearm blood flow (FBF) was measured during intra-arterial infusion of acetylcholine (ACh), and sodium nitroprusside at increasing doses. Analysis of endothelium-dependent and endothelium-independent vasodilatation was tested according to rs1050283 polymorphism. In hypertensive patients, ACh-stimulated FBF is significantly reduced in T allele carriers (P < 0.0001), even when the allelic imbalance assay indicates an overexpression of C allele. In healthy subjects, there is no significant difference for ACh-dependent vasodilatation among genotypic groups (P = 0.660). In essential hypertensive patients, the T allele of OLR1/LOX-1 gene is strongly associated with an impaired endothelium-dependent vasodilatation, a powerful predictor of cardiovascular events.

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

Similar content being viewed by others

References

  1. Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, McQueen M, Budaj A, Pais P, Varigos J, Lisheng L; INTERHEART Study Investigators (2004) Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 364:937–952

    Article  Google Scholar 

  2. Wattanakit K, Folsom AR, Chambless LE, Nieto FJ (2005) Risk factors for cardiovascular event recurrence in the Atherosclerosis Risk in Communities (ARIC) study. Am Heart J 149:606–612

    Article  PubMed  Google Scholar 

  3. Smith SC Jr, Milani RV, Arnett DK, Crouse JR III, McGrae McDermott M, Ridker PM, Rosenson RS, Taubert KA, Wilson PWF (2004) Atherosclerotic vascular disease conference writing group II: risk factors. Circulation 109:2613–2616

    Article  PubMed  Google Scholar 

  4. Perticone F, Ceravolo R, Pujia A, Ventura G, Iacopino S, Scozzafava A, Ferraro A, Chello M, Mastroroberto P, Verdecchia P, Schillaci G (2001) Prognostic significance of endothelial dysfunction in hypertensive patients. Circulation 104:191–196

    Article  CAS  PubMed  Google Scholar 

  5. Lerman A, Zeiher AM (2205) Endothelial function: cardiac events. Circulation 111:363–368

    Article  Google Scholar 

  6. Perticone F, Sciacqua A, Maio R, Perticone M, Maas R, Boger RH, Tripepi G, Sesti G, Zoccali C (2005) Asymmetric dimethylarginine, l-arginine, and endothelial dysfunction in essential hypertension. J Am Coll Cardiol 46:518–523

    Article  CAS  PubMed  Google Scholar 

  7. Perticone F, Ceravolo R, Maio R, Ventura G, Zingone A, Perrotti N, Mattioli PL (1998) Angiotensin-converting enzyme gene polymorphism is associated with endothelium-dependent vasodilation in never treated hypertensive patients. Hypertension 31:900–905

    Article  CAS  PubMed  Google Scholar 

  8. Perticone F, Sciacqua A, Scozzafava A, Ventura G, Laratta E, Pujia A, Federici M, Lauro R, Sesti G (2004) Impaired endothelial function in never-treated hypertensive subjects carrying the Arg972 polymorphism in the insulin receptor substrate-1 gene. J Clin Endocrinol Metab 89:3606–3609

    Article  CAS  PubMed  Google Scholar 

  9. Perticone F, Sciacqua A, Barlassina C, Del Vecchio L, Signorello MC, Dal Fiume C, Andreozzi F, Sesti G, Cusi D (2007) Gly460Trp alpha-adducin gene polymorphism and endothelial function in untreated hypertensive patients. J Hypertens 25:2234–2239

    Article  CAS  PubMed  Google Scholar 

  10. Witztum JL, Steinberg D (1991) Role of oxidized low density lipoprotein in atherogenesis. J Clin Invest 88:1785–1792

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Chen XP, Zhang TT, Du GH (2007) Lectin-like oxidized low-density lipoprotein receptor-1, a new promising target for the therapy of atherosclerosis? Cardiovasc Drug Rev 25:146–161

    Article  CAS  PubMed  Google Scholar 

  12. Cominacini L, Pasini AF, Garbin U, Davoli A, Tosetti ML, Campagnola M, Rigoni A, Pastorino AM, Lo Cascio V, Sawamura T (2000) Oxidized low density lipoprotein (ox-LDL) binding to ox-LDL receptor-1 in endothelial cells induces the activation of NF-kappa B through an increased production of intracellular reactive oxygen species. J Biol Chem 275:12633–12638

    Article  CAS  PubMed  Google Scholar 

  13. Li D, Mehta JL (2000) Upregulation of endothelial receptor for oxidized LDL (LOX-1) by oxidized LDL and implications in apoptosis of human coronary artery endothelial cells: evidence from use of antisense LOX-1 mRNA and chemical inhibitors. Arterioscler Thromb Vasc Biol 20:1116–1122

    Article  CAS  PubMed  Google Scholar 

  14. Cominacini L, Rigoni A, Pasini AF, Garbin U, Davoli A, Campagnola M, Pastorino AM, Lo Cascio V, Sawamura T (2001) The binding of oxidized low density lipoprotein (ox-LDL) to ox-LDL receptor-1 reduces the intracellular concentration of nitric oxide in endothelial cells through an increased production of superoxide. J Biol Chem 276:13750–13755

    CAS  PubMed  Google Scholar 

  15. Aoyama T, Sawamura T, Furutani Y, Matsuoka R, Yoshida MC, Fujiwara H, Masaki T (1999) Structure and chromosomal assignment of the human lectin-like oxidized low-density-lipoprotein receptor-1 (LOX-1) gene. Biochem J 339:177–184

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Chen M, Narumiya S, Masaki T, Sawamura T (2001) Conserved C-terminal residues within the lectin-like domain of LOX-1 are essential for oxidized low-density-lipoprotein binding. Biochem J 355:289–296

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Luedecking-Zimmer E, DeKosky ST, Chen Q, Barmada MM, Kamboh MI (2002) Investigation of oxidized LDL-receptor 1 (OLR1) as the candidate gene for Alzheimer’s disease on chromosome 12. Hum Genet 111:443–451

    Article  CAS  PubMed  Google Scholar 

  18. Mango R, Clementi F, Borgiani P, Forleo GB, Federici M, Contino G, Giardina E, Garza L, Fahdi IE, Lauro R, Mehta JL, Novelli G, Romeo F (2003) Association of single nucleotide polymorphisms in the oxidized LDL receptor 1 (OLR1) gene in patients with acute myocardial infarction. J Med Genet 40:933–936

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Puccetti L, Pasqui AL, Bruni F, Pastorelli M, Ciani F, Palazzuoli A, Pontani A, Ghezzi A, Auteri A (2007) Lectin-like oxidized-LDL receptor-1 (LOX-1) polymorphisms influence cardiovascular events rate during statin treatment. Int J Cardiol 119:41–47

    Article  CAS  PubMed  Google Scholar 

  20. Ohmori R, Momiyama Y, Nagano M, Taniguchi H, Egashira T, Yonemura A, Nakamura H, Kondo K, Ohsuzu F (2004) An oxidized low-density lipoprotein receptor gene variant is inversely associated with the severity of coronary artery disease. Clin Cardiol 27:641–644

    Article  PubMed  Google Scholar 

  21. Chen Q, Reis SE, Kammerer C, Craig WY, LaPierre SE, Zimmer EL, McNamara DM, Pauly DF, Sharaf B, Holubkov R, Bairey Merz CN, Sopko G, Bontempo F, Kamboh MI (2003) Genetic variation in lectin-like oxidized low-density lipoprotein receptor 1 (LOX1) gene and the risk of coronary artery disease. Circulation 107:3146–3151

    Article  CAS  PubMed  Google Scholar 

  22. Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, Grassi G, Heagerty AM, Kjeldsen SE, Laurent S, Narkiewicz K, Ruilope L, Rynkiewicz A, Schmieder RE, Boudier HA, Zanchetti A; ESH-ESC Task Force on the Management of Arterial Hypertension (2007) 2007 ESH-ESC practice guidelines for the management of arterial hypertension: ESH-ESC task force on the management of arterial hypertension. J Hypertens 25:1105–1187

    Google Scholar 

  23. Panza JA, Quyyumi AA, Brush JE Jr, Epstein SE (1990) Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med 323:22–27

    Article  CAS  PubMed  Google Scholar 

  24. Barbaux S, Poirier O, Godefroy T, Kleinert H, Blankenberg S, Cambien F, Tiret L (2007) Differential haplotypic expression of the interleukin-18 gene. Eur J Hum Genet 15:856–863

    Article  CAS  PubMed  Google Scholar 

  25. Mango R, Biocca S, del Vecchio F, Clementi F, Sangiuolo F, Amati F, Filareto A, Grelli S, Spitalieri P, Filesi I, Favalli C, Lauro R, Mehta JL, Romeo F, Novelli G (2005) In vivo and in vitro studies support that a new splicing isoform of OLR1 gene is protective against acute myocardial infarction. Circ Res 97:152–158

    Article  CAS  PubMed  Google Scholar 

  26. Lind L, Sarabi M, Millgård J, Kahan T (2002) Endothelium-dependent vasodilation is impaired in apparently healthy subjects with a family history of miocardial infarction. J Cardiovasc Risk 9:53–57

    Article  PubMed  Google Scholar 

  27. Rossi GP, Taddei S, Virdis A, Cavallin M, Ghiadoni L, Favilla S, Versari D, Sudano I, Pessina AC, Salvetti A (2003) The T-786C and Glu298Asp polymorphisms of the endothelial nitric oxide gene affect the forearm blood flow responses of Caucasian hypertensive patients. J Am Coll Cardiol 41:938–945

    Article  CAS  PubMed  Google Scholar 

  28. Cusi D, Barlassina C, Azzani T, Casari G, Citterio L, Devoto M, Devoto M, Glorioso N, Lanzani C, Manunta P, Righetti M, Rivera R, Stella P, Troffa C, Zagato L, Bianchi G (1997) Polymorphisms of alpha-adducin and salt sensitivity in patients with essential hypertension. Lancet 349:1353–1357

    Article  CAS  PubMed  Google Scholar 

  29. Colles SM, Maxson JM, Carlson SG, Chisolm GM (2001) Oxidized LDL-induced injury and apoptosis in atherosclerosis. Potential roles for oxysterols. Trends Cardiovasc Med 11:131–138

    Article  CAS  PubMed  Google Scholar 

  30. Brinkley TE, Kume N, Mitsuoka H, Brown MD, Phares DA, Ferrell RE, Kita T, Hagberg JM (2008) Variation in the human lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1) gene is associated with plasma soluble LOX-1 levels. Exp Physiol 93:1085–1090

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Puccetti L, Bruni F, Pasqui AL, Pastorelli M, Ciani F, Palazzuoli A, Acampa M, Auteri A (2008) Genetic influence in antithrombotic actions of atorvastatin in hypercholesterolaemia. Eur J Clin Invest 38:11–16

    Article  CAS  PubMed  Google Scholar 

Download references

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Department of Medical and Surgical Sciences, University Magna Græcia of Catanzaro, V.le Europa, 88100, Catanzaro, Italy

    Angela Sciacqua, Ivan Presta, Maria Perticone, Eliezer J. Tassone, Francesco Andreozzi, Giorgio Sesti & Francesco Perticone

  2. Dipartimento di Biomedicina e Prevenzione, Sezione di Genetica, Università degli Studi di Roma Tor Vergata, Rome, Italy

    Maria Chiara Quitadamo & Federica Carla Sangiuolo

Authors
  1. Angela Sciacqua
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ivan Presta
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maria Perticone
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eliezer J. Tassone
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Francesco Andreozzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Maria Chiara Quitadamo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Federica Carla Sangiuolo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Giorgio Sesti
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Francesco Perticone
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Francesco Perticone.

Additional information

A. Sciacqua and I. Presta have equally contributed to the work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sciacqua, A., Presta, I., Perticone, M. et al. 3′-UTR OLR1/LOX-1 gene polymorphism and endothelial dysfunction: molecular and vascular data in never-treated hypertensive patients. Intern Emerg Med 9, 273–281 (2014). https://doi.org/10.1007/s11739-012-0857-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11739-012-0857-y

Keywords

Search

Navigation