Untargeted Metabolomics Provides Insight into the Mechanisms Underlying Resistant Hypertension

Author(s): Renata Wawrzyniak, Arlette Yumba Mpanga, Wiktoria Struck-Lewicka, Marta Kordalewska, Katarzyna Polonis, Małgorzata Patejko, Monika Mironiuk, Anna Szyndler, Marzena Chrostowska, Michał Hoffmann, Ryszard T. Smoleński, Roman Kaliszan, Krzysztof Narkiewicz, Michał J. Markuszewski*.

Journal Name: Current Medicinal Chemistry

Volume 26 , Issue 1 , 2019

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Abstract:

Background: Resistant hypertension (RH) affects about 15-20% of treated hypertensive patients worldwide. RH increases the risk of cardiovascular events such as myocardial infarction and stroke by 50%. The pathological mechanisms underlying resistance to treatment are still poorly understood.

Objective: The main goal of this pilot study was to determine and compare plasma metabolomic profiles in resistant and non-resistant hypertensive patients.

Methods: We applied untargeted metabolomic profiling in plasma samples collected from 69 subjects with RH and 81 subjects with controlled hypertension. To confirm patients’ compliance to antihypertensive treatment, levels of selected drugs and their metabolites were determined in plasma samples with the LC-ESI-TOF/MS technique.

Results: The results showed no statistically significant differences in the administration of antihypertensive drug in the compared groups. We identified 19 up-regulated and 13 downregulated metabolites in the RH.

Conclusion: The metabolites altered in RH are linked to oxidative stress and inflammation, endothelium dysfunction, vasoconstriction and cell proliferation. Our results may generate new hypothesis about RH development and progression.

Keywords: Resistant hypertension, metabolomics, liquid chromatography, mass spectrometry, multivariate analysis, biomarker candidates.

[1]
Kearney, P.M.; Whelton, M.; Reynolds, K.; Muntner, P.; Whelton, P.K.; He, J. Global burden of hypertension: analysis of worldwide data. Lancet, 2005, 365, 217-223.
[2]
Achelrod, D.; Wenzel, U.; Frey, S. Systematic review and meta-analysis of the prevalence of resistant hypertension in treated hypertensive populations. Am. J. Hypertens., 2015, 28, 355-361.
[3]
Calhoun, D.A.; Jones, D.; Textor, S.; Goff, D.C.; Murphy, T.P.; Toto, R.D.; White, A.; Cushman, W.C.; White, W.; Sica, D.; Ferdinand, K.; Giles, T.D.; Falkner, B.; Carey, R.M. American Heart Association Professional Education Committee. Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Hypertension, 2008, 117, 510-526.
[4]
Sarafidis, P.A.; Georgianos, P.; Bakris, G.L. Resistant hypertension its identification and epidemiology. Nat. Rev. Nephrol., 2013, 9, 51-58.
[5]
Daugherty, S.L.; Powers, J.D.; Magid, D.J.; Tavel, H.M.; Masoudi, F.A.; Margolis, K.L.; O’Connor, P.J.; Selby, J.V.; Ho, P.M. Incidence and prognosis of resistant hypertension in hypertensive patients. Circulation, 2012, 125, 1635-1642.
[6]
Williams, B. Resistant hypertension: an unmet treatment need. Lancet, 2009, 374, 1296-1298.
[7]
MacMahon, S.; Peto, R.; Cutler, J.; Collins, R.; Sorlie, P.; Neaton, J.; Abbott, R.; Godwin, J.; Dyer, A.; Stamler, J. Blood pressure, stroke, and coronary heart disease. Part 1, Prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet, 1990, 335, 765-774.
[8]
Zheng, Y.; Yu, B.; Alexander, D.; Mosley, T.H.; Heiss, G.; Nettleton, J.A.; Boerwinkle, E. Metabolomics and incident hypertension among blacks: the atherosclerosis risk in communities study. Hypertension, 2013, 62, 398-403.
[9]
Menni, C.; Mangino, M.; Cecelja, M.; Psatha, M.; Brosnan, M.J.; Trimmer, J.; Mohney, R.P.; Chowienczyk, P.; Padmanabhan, S.; Spector, T.D.; Valdes, A.M. Metabolomic study of carotid-femoral pulse-wave velocity in women. J. Hypertens., 2015, 33, 791-796.
[10]
Kordalewska, M.; Markuszewski, M.J. Metabolomics in cardiovascular diseases. J. Pharm. Biomed. Anal., 2015, 113, 121-136.
[11]
Schanckenberg, L.K.; Beger, R.D. Metabolomic biomarkers: their role in the critical path. Drug Discov. Today. Technol., 2007, 4, 13-16.
[12]
Ciborowski, M.; Lipska, A.; Godzien, J.; Ferrarini, A.; Korsak, J.; Radziwon, P.; Tomasiak, M.; Barbas, C. Combination of LC−MS- and GC−MS-based metabolomics to study the effect of ozonated autohemotherapy on human blood. J. Proteome Res., 2012, 11, 6231-6241.
[13]
Warrack, B.M.; Hnatyshyn, S.; Ott, K.H.; Reily, M.D.; Sanders, M.; Zhang, H.; Drexler, D.M. Normalization strategies for metabonomic analysis of urine samples. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2009, 15, 547-552.
[14]
Dunn, W.B.; Broadhurst, D.; Begley, P.; Zelena, E.; Francis-McIntyre, S.; Anderson, N.; Brown, M.; Knowles, J.D.; Halsall, A.; Haselden, J.N.; Nicholls, A.W.; Wilson, I.D.; Kell, D.B.; Goodacre, R. Human Serum Metabolome (HUSERMET) Consortium. Procedures for large-scale metabolic profiling of serum and plasma using gas chromatography and liquid chromatography coupled to mass spectrometry. Nat. Protoc., 2011, 6, 1060-1083.
[15]
Jimenez-Contreras, E.; Torres-Salinas, D.; Moreno, R.; Banos, R.; Lopez-Cozar, E. Response Surface Methodology and its application in evaluating scientific activity. Scientometrics, 2009, 79, 201-218.
[16]
Farrell, E.K.; Chen, Y.; Barazanji, M.; Jeffries, K.A.; Cameroamortegui, F.; Merkler, D.J. Primary fatty acid amide metabolism: conversion of fatty acids and an ethanolamine in N 18 TG 2 and SCP cells 1. J. Lipid Res., 2012, 53, 247-256.
[17]
Hopps, J.J.; Dunn, W.R.; Randall, M.D. Enhanced vasorelaxant effects of the endocannabinoid-like mediator, oleamide, in hypertension. Eur. J. Pharmacol., 2012, 684, 102-107.
[18]
Ciborowski, M.; Martin-Ventura, J.L.; Meilhac, O.; Michel, J.B.; Ruperez, F.J.; Tunon, J.; Egido, J.; Barbas, C. Metabolites secreted by human atherothrombotic aneurysms revealed through a metabolomic approach. J. Proteome Res., 2011, 10, 1374-1382.
[19]
Ren, R.; Hashimoto, T.; Mizuno, M.; Takigawa, H.; Yoshida, M.; Azuma, T.; Kanazawa, K. A lipid peroxidation product 9-oxononanoic acid induces phospholipase A2 activity and thromboxane A2 production in human blood. J. Clin. Biochem. Nutr., 2013, 5, 228-233.
[20]
Pop, D.; Sitar-Tǎut, A.; Bodisz, G.; Zdrenghea, D.; Cebanu, M.; Stanca, L. Role of secretory phospholipase A2 in women with metabolic syndrome. Indian J. Med. Res., 2013, 138, 866-872.
[21]
Ding, Y.; Wu, C.C.; Garcia, V.; Dimitrova, I.; Weidenhammer, A.; Joseph, G.; Zhang, F.; Manthati, V.L.; Falck, J.R.; Capdevila, J.H.; Schwartzman, M.L. 20-HETE induces remodeling of renal resistance arterie independent of blood pressure elevation in hypertension. Am. J. Physiol. Renal Physiol., 2013, 305, 53-63.
[22]
Claire, M.; Jacotot, B.; Robert, L. Characterization of lipids associated with macromolecules of the intercellular matrix of human aorta. Connect. Tissue Res., 1976, 4, 61-71.
[23]
Bartke, N.; Hannun, Y.A. Bioactive sphingolipids: metabolism and function. J. Lipid Res., 2009, 50, 91-96.
[24]
Wu, Q.; Zhang, H.; Dong, X.; Chen, X-F.; Zhu, Z-Y.; Hong, Z-Y.; Chai, Y-F. UPLC-Q-TOF/MS based metabolomic profiling of serum and urine of hyperlipidemic rats induced by high fat diet. J. Pharm. Anal., 2014, 4, 360-367.
[25]
Pavoine, C.; Pecker, F. Sphingomyelinases: Their regulation and roles in cardiovascular pathophysiology. Cardiovasc. Res., 2009, 82, 175-183.
[26]
Thijs, L.; Fagard, R.; Forette, F.; Nawrot, T.; Staessen, J.A. Are low dehydroepiandrosterone sulphate levels predictive for cardiovascular diseases? A review of prospective and retrospective studies. Acta Cardiol., 2003, 58, 403-410.
[27]
Nikolic, S.B.; Sharman, J.E.; Adams, M.J.; Edwards, L.M. Metabolomics in hypertension. J. Hypertens., 2014, 32, 1159-1169.
[28]
Mitchell, B.M.; Dorrance, A.M.; Webb, R.C. Phenylalanine improves dilation and blood pressure in GTP cyclohydrolase inhibition-induced hypertensive rats. J. Cardiovasc. Pharmacol., 2004, 43, 758-763.
[29]
Pelley, J.W.; Goljan, E.F. Rapid Review Biochemistry: With student consult, 3rd ed; Elsevier: Philadelphia, 2011.
[30]
Sakurai, H. Urate transporters in the genomic era. Curr. Opin. Nephrol. Hypertens., 2013, 22, 545-550.
[31]
Mazzali, M.; Kanbay, M.; Segal, M.S.; Shafiu, M.; Jalal, D.; Feig, D.I.; Johnson, R.J. Uric acid and hypertension: Cause or effect? Curr. Rheumatol. Rep., 2010, 12, 108-117.
[32]
Feig, D.I. The role of uric acid in the pathogenesis of hypertension in the young. J. Clin. Hypertens., 2012, 14, 346-352.


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Article Details

VOLUME: 26
ISSUE: 1
Year: 2019
Page: [232 - 243]
Pages: 12
DOI: 10.2174/0929867324666171006122656

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