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Association of single nucleotide polymorphisms in endothelin family genes with the progression of atherosclerosis in patients with essential hypertension

Journal of Human Hypertension volume 21, pages 883–892 (2007)Cite this article

Abstract

Endothelin-1 (ET-1) is a potent vasoconstrictive peptide and its activity is mediated by the receptors ET type A (EDNRA) and ET type B (EDNRB). Although ET-1 is thought to play an important role in the development of atherosclerosis, it remains unclear whether polymorphisms of ET-1 family genes, including the ET-1 gene (EDN1), EDNRA, EDNRB and the genes for endothelin converting enzymes 1 and 2 (ECE1 and ECE2), are associated with the progression of atherosclerosis. We investigated the relationship between 11 single nucleotide polymorphisms (SNPs) of ET-1 family genes (including three in EDN1, one in EDNRA, two in EDNRB, four in ECE1 and one in ECE2) and atherosclerotic changes assessed using pulse wave velocity (PWV) and carotid ultrasonography in 630 patients with essential hypertension (EHT). In male subjects, we found significant differences in brachial-ankle PWV (baPWV) in additive and recessive models in EDNRB-rs5351 after Bonferroni correction. Also in male subjects, there were significant differences in mean intima-media thickness (IMT) in additive and recessive models in EDNRA-rs5333 after Bonferroni correction. We found no significant correlation between any SNPs in the ET family genes and baPWV, IMT and Plaque score (PS) in female subjects. Furthermore, after multiple logistic regression analysis, only EDNRB-rs5351 indicated as an independent risk of atherosclerosis in male hypertensive subjects. Of the endothelin-related genes, EDNRB-rs5351 was the most susceptible SNP associated with atherosclerosis in male hypertensives, and the genetic background may be involved in the progression of atherosclerosis in EHT patients.

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References

  1. Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988; 332: 411–415.

    Article  CAS  Google Scholar 

  2. Lerman A, Edwards BS, Hallett JW, Heublen DM, Sandberg SM, Burnett Jr JC et al. Circulating and tissue endothelin immunoreactivity in advanced atherosclerosis. N Engl J Med 1991; 325: 997–1001.

    Article  CAS  Google Scholar 

  3. Hirai Y, Adachi H, Fujita Y, Hiratsuka A, Enomoto M, Imaizumi T . Plasma endothelin-1 level is related to renal function and smoking status but not to blood pressure: an epidemiological study. J Hypertens 2004; 22: 713–718.

    Article  CAS  Google Scholar 

  4. Takase H, Moreau P, Lüschner TF . Endothelin receptor subtypes in small arteries. Studies with FR 139317 and bosentan. Hypertension 1995; 25: 739–743.

    Article  CAS  Google Scholar 

  5. Arai H, Hori S, Aramori I, Nakanishi S . Cloning and expression of a cDNA encoding an endothelin receptor. Nature 1990; 348: 730–732.

    Article  CAS  Google Scholar 

  6. Hirata Y, Emori T, Eguchi S, Kanno K, Imai T, Ohta K et al. Endothelin receptor subtype B mediates synthesis of nitric oxide by cultured bovine endothelial cells. J Clin Invest 1993; 92: 1367–1373.

    Article  Google Scholar 

  7. Warner TD . Characterization of endothelin synthetic pathways and receptor subtypes: physiological and pathological implications. Eur Heart J 1993; 14 (suppl I): 42–47.

    CAS  PubMed  Google Scholar 

  8. Fukuroda T, Fujikawa T, Ozaki S, ishikawa K, yano M, Nishikibe M . Clearance of circulating endothelin-1 by ETB receptors in rats. Biochem Biophy Res Commun 1994; 199: 1461–1465.

    Article  CAS  Google Scholar 

  9. Morris MJ, Cox HS, Lambert GW, Kaye DM, Jennings GL, Meredith IT et al. Region-specific neuropeptide Y overflows at rest and during sympathetic activation in humans. Hypertension 1997; 29: 137–143.

    Article  CAS  Google Scholar 

  10. Nohria A, Garrett L, Johnson W, Kinlay S, Ganz P, Creager MA . Endothelin-1 and vascular tone in subjects with atherogenic risk factors. Hypertension 2003; 42: 43–47.

    Article  CAS  Google Scholar 

  11. Maeda S, Miyauchi T, Iemitsu M, Sugawara J, Nagata Y, Goto K . Resistance exercise training reduces plasma endothelin-1 concentration in healthy young humans. J Cardiovasc Pharmacol TM 2004; 44 (suppl 1): S443–S446.

    Article  CAS  Google Scholar 

  12. Blacher J, Asmar R, Djane S, London GM, Safer ME . Aortic pulse wave velocity as a marker of cardiovascular risk in hypertensive patients. Hypertension 1999; 33: 1111–1117.

    Article  CAS  Google Scholar 

  13. McEniery CM, Qasem A, Schmitt M, Avolio AP, Cockcroft JR, Wilkinson IB . Endothelin-1 regulates arterial pulse wave velocity in vivo. J Am Coll Cardiol 2003; 42: 1975–1981.

    Article  CAS  Google Scholar 

  14. Vuurmans TJL, Boer P, Koomans HA . Effects of endothelin-1 and endothelin-1 receptor blockade on cardiac output, aortic pressure, and pulse wave velocity in humans. Hypertension 2003; 41: 1253–1258.

    Article  CAS  Google Scholar 

  15. Takiuchi S, Mannami T, Miyata T, Kamide K, Tanaka C, Kokubo Y et al. Identification of 21 single nucleotide polymorphisms in human hepatocyte growth factor gene and association with blood pressure and carotid atherosclerosis in Japanese population. Atherosclerosis 2004; 173: 301–307.

    Article  CAS  Google Scholar 

  16. Tanaka C, Kamide K, Takiuchi S, Kawano Y, Miyata T . An alternative fast and convenient genotyping method for the screening of angiotensin converting enzyme gene polymorphisms. Hypertens Res 2003; 26: 301–306.

    Article  CAS  Google Scholar 

  17. Handa N, Matsumoto M, Maeda H, Hougaku H, Ogawa S, Fukunaga R et al. Ultrasonic evaluation of early carotid atherosclerosis. Stroke 1990; 21: 1567–1572.

    Article  CAS  Google Scholar 

  18. Inoue A, Yanagisawa M, Kimura S, Katsuya Y, Miyauchi T, Goto K et al. The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes. Proc Natl Acad Sci USA 1989; 86: 2863–2867.

    Article  CAS  Google Scholar 

  19. Tiret L, Poirier O, Hallet V, McDonagh TH, Morrison C, McMurray JJ et al. The Lys198Asn polymorphism in the endothelin-1 gene is associated with blood pressure in overweight people. Hypertension 1999; 33: 1169–1174.

    Article  CAS  Google Scholar 

  20. Asai T, Ohkubo T, Katsuya T, Higaki J, Fu Y, Fukuda M et al. Endothelin-1 gene variant associates with blood pressure in obese Japanese subjects. The Ohasama study. Hypertension 2001; 38: 1321–1324.

    Article  CAS  Google Scholar 

  21. Jin JJ, Nakura J, Wu Z, Yamamoto M, Abe M, Tabara Y et al. Association of endothelin-1 gene variant with hypertension. Hypertension 2003; 41: 163–167.

    Article  CAS  Google Scholar 

  22. Tatchum-Talom R, Martel C, Labrie C, Labrie F, Marette A . Gender differences in hemodynamic responses to endothelin-1. J Cardiovasc Pharmacol 2000; 36 (suppl 1): S102–S104.

    Article  CAS  Google Scholar 

  23. Jiang C, Sarrel PM, Poole-Wilson PA, Collins P . Acute effect of 17-estradiol on rabbit coronary artery contractile responses to endothelin-1. Am J Physiol 1992; 263: H271–H275.

    CAS  PubMed  Google Scholar 

  24. Lajemi M, Gautier S, Poirier O, Baguet JP, Mimran A, Gosse P et al. Endothelin gene variants and aortic and cardiac structure in never-treated hypertensives. Am J Hypertens 2001; 14: 755–760.

    Article  CAS  Google Scholar 

  25. Funalot B, Courbon D, Brousseau T, Poirier O, Berr C, Cambien F et al. Genes encoding endothelin-converting enzyme-1 and endothelin- interact to influence blood pressure in women: The EVA study. J Hypertens 2004; 22: 739–743.

    Article  CAS  Google Scholar 

  26. Blacher J, Protogerou AD, Safer ME . Large artery stiffness and antihypertensive agents. Curr Pharm Des 2005; 25: 3317–3326.

    Article  Google Scholar 

  27. Campia U, Cardillo C, Panza JA . Ethnic differences in the vasoconstrictor activity of endogenous endothelin-1 in hypertensive patients. Circulation 2004; 109: 3191–3195.

    Article  Google Scholar 

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Acknowledgements

This study was supported by the Programme for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO) of Japan, and a Grant-in Aid and a Research Grant for Cardiovascular Diseases (16C-1) from the Japanese Ministry of Health, Labour, and Welfare of Japan. We thank Chihiro Tanaka and Mariko Banno for their excellent technical assistance and to Erumu Hayase and Chikako Tokudome for their administrative help.

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Authors and Affiliations

  1. Division of Hypertension and Nephrology, National Cardiovascular Center, Suita, Osaka, Japan

    H Yasuda, K Kamide, S Takiuchi, T Matayoshi, J Yang, Y Miwa, M Yoshii, T Horio, F Yoshihara, S Nakamura, H Nakahama & Y Kawano

  2. Research Institute, National Cardiovascular Center, Suita, Osaka, Japan

    H Hanada, A Kada, J Yang & T Miyata

  3. Department of Cardiovascular, Respiratory and Metabolic Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Sakuragaoka, Kagoshima, Japan

    C Tei

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  1. H Yasuda
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Correspondence to K Kamide.

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Yasuda, H., Kamide, K., Takiuchi, S. et al. Association of single nucleotide polymorphisms in endothelin family genes with the progression of atherosclerosis in patients with essential hypertension. J Hum Hypertens 21, 883–892 (2007). https://doi.org/10.1038/sj.jhh.1002234

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  • DOI: https://doi.org/10.1038/sj.jhh.1002234

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