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Macro- and Microelement Status in Animal and Human Hypertension: the Role of the ACE Gene I/D Polymorphism

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Abstract

Genetic factors that predispose to hypertension may contribute to element disturbances observed in hypertensive patients. We tested the hypothesis that the deletion allele of the angiotensin-converting enzyme (ACE) gene is associated with element imbalances in hypertension. The concentrations of elements in genetically predisposed to hypertension rats (SHRs) and their controls (WKY rats) were also examined. ICP-MS was used for elemental analysis of human hair and animal fur. Genotyping was performed by PCR. We also measured micronuclei frequency and distribution of peripheral blood leukocytes in cell cycle phases by flow cytometry and studied the correlations of these parameters with element contents. In general, the tendency for higher levels of toxic and lower levels of essential elements is observed in hypertension, specifically in patients carrying the D allele. Hypertensive men had significantly higher Be, V, Cr, As, Mo, Ag, Sb, and Na levels and lower Ca, Zn, Ba, and U levels compared with control subjects; the differences were not significant for Mg, Al, K, Mn, Fe, Co, Ni, Cu, Se, Cd, Tl, Pb, and Th. The D allele was associated with higher Be, Mo, and Th levels and lower Zn, Se, and Tl levels. The concentrations of Ca, Co, Mo and U were higher in SHR than those in the WKY rats. Mo, an antagonist of Cu, positively correlated with the S-phase cells, and Cu positively correlated with micronuclei frequency. The results suggest an involvement of the ACE I/D polymorphism in element imbalances in hypertension and attract attention to the possible significant role of genetic factors in Mo accumulation.

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References

  1. A global brief on Hypertension. World Health Organisation (2013) http://ish-world.com/downloads/pdf/global_brief_hypertension.pdf. Accessed 25 December 2016

  2. Lim SS, Vos T, Flaxman AD et al (2012) A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380(9859):2224–2260. doi:10.1016/S0140-6736(12)61766-8

    Article  PubMed  PubMed Central  Google Scholar 

  3. Ketonen J, Merasto S, Paakkari I, Mervaala EM (2005) High sodium intake increases vascular superoxide formation and promotes atherosclerosis in apolipoprotein E-deficient mice. Blood Press 4(6):373–382. doi:10.1080/08037050500383687

    Article  Google Scholar 

  4. Tubeck S (2006) Role of trace elements in primary arterial hypertension: is mineral water style or prophylaxis? Biol Trace Elem Res 114:1–5. doi:10.1385/BTER:114:1:1

    Article  Google Scholar 

  5. Goch A (2005) Concentration of elements in plasma of patients with essential hypertension. Pol Arch Med Wewn 114(4):947–952

    CAS  PubMed  Google Scholar 

  6. Afridi HI, Kazi TG, Talpur FN, Kazi A, Arain SS, Arain SA, Brahman KD, Panhwar AH, Naeemullah SM, Ali J (2014a) Interaction between essential elements selenium and zinc with cadmium and mercury in samples from hypertensive patients. Biol Trace Elem Res 160(2):185–196. doi:10.1007/s12011-014-0048-y

    Article  CAS  PubMed  Google Scholar 

  7. Gonzalez-Munoz MJ, Sanchez-Muniz FJ, Rodenas S, Sevillano MI, Marin MTL, Bastida S (2010) Differences in metal and metalloid content in the hair of normo- and hypertensive postmenopausal women. Hypertens Res 33:219–224. doi:10.1038/hr.2009.221

    Article  CAS  PubMed  Google Scholar 

  8. Gouaref I, Bellahsene Z, Zekri S, Alamir B, Koceir EA (2016) The link between trace elements and metabolic syndrome/oxidative stress in essential hypertension with or without type 2 diabetes. Ann Biol Clin (Paris) 74(2):233–243. doi:10.1684/abc.2016.1126

    Google Scholar 

  9. Von Haehling S, Jankowska EA, van Veldhuisen DJ, Ponikowski P, Anker SD (2015) Iron deficiency and cardiovascular disease. Nat Rev Cardiol 12(11):659–669. doi:10.1038/nrcardio.2015.109

    Article  CAS  PubMed  Google Scholar 

  10. Tomita H (1990) Trace elements in clinical medicine proceedings of the second meeting of the International Society for Trace Element Research in Humans (ISTERH) August 28–September 1, 1989. Springer-Verlag, Tokyo

    Google Scholar 

  11. Hitomi H, Kiyomoto H, Nishiyama A (2007) Angiotensin II and oxidative stress. Curr Opin Cardiol 22(4):311–315. doi:10.1097/HCO.0b013e3281532b53

    Article  PubMed  Google Scholar 

  12. Rigat B, Hubert C, Corvo P, Soubrier F (1992) PCR detection of the insertion/deletion polymorphism of the human angiotensin converting enzyme gene (DCP1) (dipeptidyl carboxypeptidase 1). Nucl Acids Res 20(6):1433

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F (1990) An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 86(4):1343–1346. doi:10.1172/JCI114844

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lachurié ML, Azizi M, Guyene TT, Alhenc-Gelas F, Ménard J (1995) Angiotensin-converting enzyme gene polymorphism has no influence on the circulating renin-angiotensin-aldosterone system or blood pressure in normotensive subjects. Circulation 91(12):2933–2942. doi:10.1161/01.CIR.91.12.2933

    Article  PubMed  Google Scholar 

  15. O'Donnell CJ, Lindpaintner K, Larson MG, Rao VS, Ordovas JM, Schaefer EJ, Myers RH, Levy D (1998) Evidence for association and genetic linkage of the angiotensinconverting enzyme locus with hypertension and blood pressure in men but not women in the Framingham Heart Study. Circulation 97(18):1766–1772. doi:10.1161/01.CIR.97.18.1766

    Article  PubMed  Google Scholar 

  16. Krishnana R, Sekara D, Karunanithyb S, Subramaniumb S (2016) Association of angiotensin converting enzyme gene insertion/deletion polymorphism with essential hypertension in south Indian population. Genes & Diseases 3(2):159–163

    Article  Google Scholar 

  17. Mao S, Li C (2015) Hypotensive and angiotensin-converting enzyme inhibitory activities of eisenia fetida extract in spontaneously hypertensive rats. Evid Based Complement Alternat Med 2015:1–7. doi:10.1155/2015/349721

    Article  Google Scholar 

  18. Zimmer J, Hawlitschek C, Rabald S, Hagendorff A, Zimmer HG, Rassler B (2015) Effects of late-onset and long-term captopril and nifedipine treatment in aged spontaneously hypertensive rats: echocardiographic studies. Hypertens Res 38(11):716–722. doi:10.1038/hr.2015.68

    Article  CAS  PubMed  Google Scholar 

  19. Alissa EM, Ferns GA (2011) Heavy metal poisoning and cardiovascular disease. J Toxicol 2011:870125. doi:10.1155/2011/870125

    Article  PubMed  PubMed Central  Google Scholar 

  20. Wołowiec P, Michalak I, Chojnacka K, Mikulewicz M (2013) Hair analysis in health assessment. Clin Chim Acta 419:139–171. doi:10.1016/j.cca.2013.02.001

    Article  PubMed  Google Scholar 

  21. Chalmers J, MacMahon S, Mancia G, Whitworth J, Beilin L, Hansson L, Neal B, Rodgers A, Ni Mhurchu C, Clark T (1999) 1999 World Health Organization-International Society of Hypertension Guidelines for the management of hypertension. Guidelines sub-committee of the World Health Organization. Clin Exp Hypertens 21(5–6):1009–1060. doi:10.3109/10641969909061028

    CAS  PubMed  Google Scholar 

  22. Hedayati SS, Minhajuddin AT, Ijaz A, Moe OW, Elsayed EF, Reilly RF, Huang CL (2012) Association of Urinary Sodium/potassium ratio with blood pressure: sex and racial differences. Clin J Am Soc Nephrol 7(2):315–322. doi:10.2215/CJN.02060311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Biino G, Parati G, Concas MP, Adamo M, Angius A, Vaccargiu S, Pirastu M (2013) Environmental and genetic contribution to hypertension prevalence: data from an epidemiological survey on Sardinian genetic isolates. PLoS One 8(3):e59612. doi:10.1371/journal.pone.0059612

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Fenech M, Kirsch-Volders M, Natarajan AT, Surralles J, Crott JW, Parry J, Norppa H, Eastmond DA, Tucker JD, Thomas P (2011) Molecular mechanisms of micronucleus, nucleoplasmic bridge and nuclear bud formation in mammalian and human cells. Mutagenesis 26(1):125–132. doi:10.1093/mutage/geq052

    Article  CAS  PubMed  Google Scholar 

  25. Bartek J, Lukas C, Lukas J (2004) Checking on DNA damage in S phase. Nat Rev Mol Cell Biol 5(10):792–804. doi:10.1038/nrm1493

    Article  CAS  PubMed  Google Scholar 

  26. Panhwar AH, Kazi TG, Afridi HI, Talpur FN, Arain S, Kazi N (2014) Distribution of potassium, calcium, magnesium, and sodium levels in biological samples of Pakistani hypertensive patients and control subjects. Clin Lab 60(3):463–474

    CAS  PubMed  Google Scholar 

  27. McCarron DA, Morris CD, Henry HJ, Stanton JL (1984) Blood pressure and nutrient intake in the United States. Science 224:1392–1398

    Article  CAS  PubMed  Google Scholar 

  28. Shiue I (2014) Higher urinary heavy metal, phthalate, and arsenic but not parabens concentrations in people with high blood pressure, U.S. NHANES, 2011–2012. Int J Environ Res Public Health 11(6):5989–5999. doi:10.3390/ijerph110605989

    Article  PubMed  PubMed Central  Google Scholar 

  29. Afridi HI, Kazi TG, Talpur FN, Arain S, Arain SS, Kazi N, Panhwar AH (2014b) Distribution of arsenic, cadmium, lead, and nickel levels in biological samples of Pakistani hypertensive patients and control subjects. Clin Lab 60(8):1309–1318

    CAS  PubMed  Google Scholar 

  30. Sun L, Wang X, Yao H, Li W, Son YO, Luo J, Liu J, Zhang Z (2012) Reactive oxygen species mediate Cr(VI)-induced S phase arrest through p53 in human colon cancer cells. J Environ Pathol Toxicol Oncol 31(2):95–107

    Article  CAS  PubMed  Google Scholar 

  31. Zhang M, Luo J, Zhang C, Cao H, Xia B, Hu G (2016) Alterations in antioxidant function and cell apoptosis in spleens of duck exposed to molybdenum or/and cadmium. The Korean Society of Veterinary Science. http://www.vetsci.org/journal/view.html?uid=1127&vmd=Full. Accessed 14 March 2017

  32. Kumar A, Mishra P, Ghosh S, Sharma P, Ali M, Pandey BN, Mishra KP (2008) Thorium-induced oxidative stress mediated toxicity in mice and its abrogation by diethylenetriamine pentaacetate. Int J Radiat Biol 84(4):337–349. doi:10.1080/09553000801983133

    Article  CAS  PubMed  Google Scholar 

  33. Solenkova NV, Newman JD, Berger JS, Thurston G, Hochman JS, Lamas GA (2014) Metal pollutants and cardiovascular disease: mechanisms and consequences of exposure. Am Heart J 168(6):812–822. doi:10.1016/j.ahj.2014.07.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Sauk JJ, Somerman MJ (1991) Physiology of bone: mineral compartment proteins as candidates for environmental perturbation by lead. Environ Health Perspect 91:9–16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Andrews GK (2000) Regulation of metallothionein gene expression by oxidative stress and metal ions. Biochem Pharmacol 59(1):95–104

    Article  CAS  PubMed  Google Scholar 

  36. Lahera V, Cachofeiro V, de Las HN (2011) Interplay of hypertension, inflammation, and angiotensin II. Am J Hypertens 24(10):1059. doi:10.1038/ajh.2011.142

    Article  CAS  PubMed  Google Scholar 

  37. Mak IT, Landgraf KM, Chmielinska JJ, Weglicki WB (2012) Angiotensin II promotes iron accumulation and depresses PGI2 and NO synthesis in endothelial cells: effects of losartan and propranolol analogs. Can J Physiol Pharmacol 90(10):1413–1418. doi:10.1139/y2012-104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Degani H, Lenkinski RE (1980) Ionophoric properties of angiotensin II peptides. Nuclear magnetic resonance kinetic studies of the hormone-mediated transport of manganese ions across phosphatidylcholine bilayers. Biochemistry 19(15):3430–3434

    Article  CAS  PubMed  Google Scholar 

  39. Ekmekci OB, Donma O, Tunckale A (2003) Angiotensin-converting enzyme and metals in untreated essential hypertension. Biol Trace Elem Res 95(3):203–210. doi:10.1385/BTER:95:3:203

    Article  CAS  PubMed  Google Scholar 

  40. Lau K, Langman CB, Gafter U, Dudeja PK, Brasitus TA (1986) Increased calcium absorption in prehypertensive spontaneously hypertensive rat. Role of serum 1,25-dihydroxyvitamin D3 levels and intestinal brush border membrane fluidity. J Clin Invest 78(4):1083–1090. doi:10.1172/JCI112664

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Shiue I, Hristova K (2014) Higher urinary heavy metal, phthalate and arsenic concentrations accounted for 3-19% of the population attributable risk for high blood pressure: US NHANES, 2009-2012. Hypertens Res 37(12):1075–1081. doi:10.1038/hr.2014.121

    Article  CAS  PubMed  Google Scholar 

  42. Rotter I, Kosik-Bogacka D, Dołęgowska B, Safranow K, Lubkowska A, Laszczyńska M (2015) Relationship between the concentrations of heavy metals and bioelements in aging men with metabolic syndrome. Int J Environ Res Public Health 12(4):3944–3961. doi:10.3390/ijerph120403944

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Brewer GJ, Dick RD, Grover DK, LeClaire V, Tseng M, Wicha M, Pienta K, Redman BG, Jahan T, Sondak VK, Strawderman M, LeCarpentier G, Merajver SD (2000) Treatment of metastatic cancer with tetrathiomolybdate, an anticopper, antiangiogenic agent: phase I study. Clin Cancer Res 6(1):1–10

    CAS  PubMed  Google Scholar 

  44. Humar R, Zimmerli L, Battegay E (2009) Angiogenesis and hypertension: an update. J Hum Hypertens 23:773–782. doi:10.1038/jhh.2009.63

    Article  CAS  PubMed  Google Scholar 

  45. Picco SJ, Abba MC, Mattioli GA, Fazzio LE, Rosa D, De Luca JC, Dulout FN (2004) Association between copper deficiency and DNA damage in cattle. Mutagenesis 19(6):453–456. doi:10.1093/mutage/geh056

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Olena Pavlyushchik.

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All procedures involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments. Written informed consent was obtained from each patient.

All applicable international, national, and institutional guidelines for the care and use of animals were followed.

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Pavlyushchik, O., Afonin, V., Fatykhava, S. et al. Macro- and Microelement Status in Animal and Human Hypertension: the Role of the ACE Gene I/D Polymorphism. Biol Trace Elem Res 180, 110–119 (2017). https://doi.org/10.1007/s12011-017-0990-6

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