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Leukocyte matrix metalloproteinase and tissue inhibitor gene expression patterns in children with primary hypertension

Abstract

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) play an important role in cardiovascular remodeling. The aim of the study was to analyze MMP/TIMP genes expression in peripheral blood leukocytes of 80 hypertensive children (15.1 ± 2.0 years) in comparison with age-matched 78 normotensive children (14.6 ± 2.0 years; n.s.). TIMP and MMP expression in peripheral blood leukocytes was assessed by quantitative real-time PCR. Hypertensive children independently of age, sex, and body mass index had greater expression of MMP-2 than normotensive controls (p = 0.0001). Patients with left ventricular hypertrophy had greater expression of MMP-14 than patients with normal left ventricular mass (p = 0.006) and TIMP-2 expression correlated with carotid wall cross-sectional area (p = 0.03; r = 0.238). MMP-14 expression correlated with BMI-SDS (p = 0.001; r = 0.371), waist circumference-SDS (p = 0.016; r = 0.290), hsCRP (p = 0.003; r = 0.350), serum HDL-cholesterol (p = 0.008; r = −0.304), and serum uric acid (p = 0.0001; r = 0.394). In conclusion, hypertensive adolescents presented significant alterations of MMP/TIMP expression pattern in comparison with normotensive peers. Moreover, altered MMP/TIMP expression was associated with hypertensive target organ damage and metabolic abnormalities.

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References

  1. Itani HA, McMaster WG, Saleh MA, Nazarewicz RR, Mikolajczyk TP, Kaszuba AM, et al. Activation of human T cells in hypertension: studies of humanized mice and hypertensive humans. Hypertension. 2016;68:123–32.

    Article  CAS  Google Scholar 

  2. Anwar MA, Shalhoub J, Lim CS, Gohel MS, Davies AH. The effect of pressure-induced mechanical stretch on vascular wall differential gene expression. J Vasc Res. 2012;49:463–78.

    Article  CAS  Google Scholar 

  3. Marchesi C, Dentali F, Nicolini E, Maresca AM, Tayebjee MH, Franz M, et al. Plasma levels of matrix metalloproteinases and their inhibitors in hypertension a systemic review and meta-analysis. J Hypertens. 2012;30:3–16.

    Article  CAS  Google Scholar 

  4. Niemirska A, Litwin M, Trojanek J, Gackowska L, Kubiszewska I, Wierzbicka A, et al. Altered matrix metalloproteinase 9 and tissue inhibitor of metalloproteinases 1 levels in children with primary hypertension. J Hypertens. 2016;34:1815–22.

    Article  CAS  Google Scholar 

  5. Lurbe E, Agabiti-Rosei E, Cruickshank JK, Dominiczak A, Erdine S, Hirth A, et al. 2016 European Society of Hypertension guidelines for the management of high blood pressure in children and adolescents. J Hypertens. 2016;34:1887–92.

    Article  CAS  Google Scholar 

  6. Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, Smiseth OA, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography. J Am Soc Echocardiogr. 2009;22:107–33.

    Article  Google Scholar 

  7. De Simone G, Deveraux RB, Daniels SR, Koren MJ, Meyer RA, Laragh JH. Effect of growth on variability of left ventricular mass assessment of allometric signals in adults and children and their capacity to predict cardiovascular risk. J Am Coll Cardiol. 1995;25:1056–62.

    Article  Google Scholar 

  8. Khoury PR, Mitsnefes M, Daniels SR, Komball TR. Age-specific reference intervals for indexed left ventricular mass in children. J Am Soc Echocardiogr. 2009;22:709–14.

    Article  Google Scholar 

  9. Jourdan C, Wuhl E, Litwin M, Fahr, Trelewicz J, Jobs K, et al. Normative values of intima-media thickness and distensibility of large arteries in healthy adolescents. J Hypertens. 2005;23:1707–15.

    Article  CAS  Google Scholar 

  10. Zimmet P, Alberti K, George MM, Tajima N, Silink M, Arslanian S, et al. The metabolic syndrome in children and adolescents - an IDF consensus report. Pediatr Diabetes. 2007;8:299–306.

    Article  Google Scholar 

  11. Kułaga Z, Litwin M, Zajączkowska MM, Wasilewska A, Morawiec-Knysak A, Różdżyńska A. et al. Comparision of waist and hip circumferences ranges in children and adolescents in Poland 7-18 y of age with cardiovascular risk thresholds: initial results of Olaf project (PL0080). Stand Med. 2008;5:473–85.

    Google Scholar 

  12. Trojanek JB, Cobos-Correa A, Diemer S, Kormann M, Schubert SC, Zhou-Suckow Z, et al. Airway mucus obstruction triggers macrophage activation and matrix metalloproteinase 12-dependent emphysema. Am J Respir Cell Mol Biol. 2014;51:709–20.

    Article  Google Scholar 

  13. Kułaga Z, Litwin M, Tkaczyk M, Palczewska I, Zajączkowska M, Zwolińska D, et al. Polish 2010 growth references for school-aged children and adolescents. Eur J Pediatr. 2011;170:599–609.

    Article  Google Scholar 

  14. Głowińska-Olszewska B, Urban M. Elevated matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 in obese children and adolescents. Metabolism. 2007;56:799–805.

    Article  Google Scholar 

  15. Belo VA, Souza-Costa DC, Lana CM, Caputo FL, Marcaccini AM, Gerlach RF, et al. Assessment of matrix metalloproteinase (MMP)-2, MMP-8, MMP-9, and their inhibitors, the tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2 in obese children and adolescents. Clin Biochem. 2009;42:984–90.

    Article  CAS  Google Scholar 

  16. Bar–Or A, Nuttall NK, Duddy M, Alter A, Ho Jin Kim HJ, et al. Analyses of all matrix metalloproteinase members in leukocytes emphasize monocytes as major inflammatory mediators multiple sclerosis. Brain. 2003;126:2738–49.

    Article  Google Scholar 

  17. Rodrigues SF, Tran ED, Fortes ZB, Schmid-Schonbein GW. Matrix metalloproteinases cleave the beta2 -adrenergic receptor in the spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol. 2010;299:H25–H35.

    Article  CAS  Google Scholar 

  18. DeLano FA, Schmid-Schonbein GW. Proteinase activity and receptor cleavage: mechanism for insulin resistance in the spontaneously hypertensive rat. Hypertension. 2008;52:415–23.

    Article  CAS  Google Scholar 

  19. Tran ED, DeLano FA, Schmid-Schonbein GW. Enhanced matrix metalloproteinase activity in the spontaneously hypertensive rat: VEGFR-2 cleavage, endothelial apoptosis, and capillary rarefaction. J Vasc Res. 2010;47:423–31.

    Article  CAS  Google Scholar 

  20. Wu KI, Schmid-Schobein GW. Nuclear factor kappa B and matrix metalloproteinase induced receptor cleavage in the spontaneously hypertensive rat. Hypertension. 2011;57:261–8.

    Article  CAS  Google Scholar 

  21. Trott WD, Harrison DG. The immune system in hypertension. Adv Physiol Educ. 2014;38:20–24.

    Article  Google Scholar 

  22. Medeiros NI, Fares RCG, Franco EP, Sousa GR, Mattos RT, Chaves AT, et al. Differential expression of matrix metalloproteinase 2,9 and cytokines by neutrophils and monocytes in trhe clinical forms of Chagas disease. PLoS Negl Trop Dis. 2017;11:e0005284. 10.1371.

    Article  Google Scholar 

  23. Itoh T, Matsuda H, Tanioka M, Kuwabara K, Itohara S, Suzuki R. The role of matrix metalloproteinase 2 and matrix metalloproteinase 9 in antibody induced arthritis. J Immunol. 2002;169:2643–7.

    Article  CAS  Google Scholar 

  24. Xue M, March L, Sambrook PN, Jackson CJ. Differential regulation of matrix metalloproteinase 2 and matrix metalloproteinase 9 by activated protein C: relevance to inflammation in rheumatoid arthritis. Arthritis Rheum. 2007;56:2864–74.

    Article  CAS  Google Scholar 

  25. Belo VA, Guimaraes DA, Castro MM. Matrix metalloproteinase 2 as a potential mediator of vascular smooth muscle cell migration and chronic vascular remodeling in hypertension. J Vasc Res. 2015;52:221–31.

    Article  CAS  Google Scholar 

  26. Spinale FG, Janicki SJ, Zile MR. Membrane associated matrix proteolysis and heart failure. Circ Res. 2013;112:195–20.

    Article  CAS  Google Scholar 

  27. Cummins PM, von Offenberg NS, Killeen MT, Birney YA, Redmond EM, Cahill P. Cyclic strain-mediated matrix metalloproteinase regulation within the vascular endothelium: a force to be reckoned with. Am J Physiol Heart Circ Physiol. 2007;292:H28–H42.

    Article  CAS  Google Scholar 

  28. Polyakova V, Hein S, Kostin S, MD, Ziegelhoeffer T, Schaper J:. Matrix metalloproteinases and their tissue inhibitors in pressure-overloaded human myocardium during heart failure progression. J Am Coll Cardiol. 2004;44:1609–18.

    Article  CAS  Google Scholar 

  29. Zervoudaki A, Economou E, Stefanadis C, Pitsavos C, Tsioufis K, Aggeli C, et al. Plasma levels of active extracellular matrix metalloproteinases 2 and 9 in patients with essential hypertension before and after antihypertensive treatment. J Hum Hypertens. 2003;17:119–24.

    Article  CAS  Google Scholar 

  30. Ishikawa J, Kario K, Matsui Y, Shibasaki S, Morinari M, Kaneda R, et al. Collagen metabolism in extracellular matrix may be involved in arterial stiffness in older hypertensive patients with left ventricular hypertrophy. Hypertens Res. 2005;28:995–1001.

    Article  CAS  Google Scholar 

  31. Odenbach J, Wang X, Cooper S, Chow FL, Oka T, Lopaschuk G, et al. MMP-2 mediates angiotensin II-induced hypertension under transcriptional control of MMP-7 and TACE. Hypertension. 2011;57:123–30.

    Article  CAS  Google Scholar 

  32. Lin J, Davis HB, Dai Q, Chou Y, Craig T, Hinojosa-Laborde C, et al. Effects of early and late chronic pressure overload on extracellular matrix remodeling. Hypertens Res. 2008;31:1225–31.

    Article  CAS  Google Scholar 

  33. Turner NA, Warburton P, O’Regan DJ, Ball SG, Porter KE. Modulatory effect of interleukin-1α on expression of structural matrix proteins, MMPs and TIMPs in human cardiac myofibroblasts: role of p38 MAP kinase. Matrix Biol. 2010;29:613–20.

    Article  CAS  Google Scholar 

  34. Harvey A, Montezano AC, Lopes RA, Rios F, Touyz RM. Vascular fibrosis in aging and hypertension: molecular mechanisms and clinical implications. Can J Cardiol. 2016;32:659–68.

    Article  Google Scholar 

  35. Litwin M, Niemirska A, Śladowska-Kozlowska J, Wierzbicka A, Janas R, Wawer ZT, et al. Regression of target organ damage in children and adolescents with primary hypertension. Pediatr Nephrol. 2010;25:2489–99.

    Article  Google Scholar 

  36. Litwin M, Feber J, Niemirska A, Michałkiewicz J. Primary hypertension is a disease of premature vascular aging associated with neuro-immuno-metabolic abnormalities. Pediatr Nephrol. 2016;31:185–94.

    Article  Google Scholar 

  37. Itoh Y. Membrane –type matrix metalloproteinases: their functions and regulations. Matrix Biol. 2015;44–46:207–23.

    Article  CAS  Google Scholar 

  38. Van Lint P, Libert C. Chemokine and cytokine processing by matrix metalloproteinases and its effect on leukocyte migration and inflammation. J Leukoc Biol. 2007;82:1375–81.

    Article  Google Scholar 

  39. Fenech M, Gavrilovic J, Malcolm P, Toms A, Turner J. The role of metalloproteinases and their tissue inhibitors in adipose tissue remodelling and whole-body lipid distribution: a cross-sectional clinical study. Lancet. 2015;385(Suppl 1):S36.

    Article  Google Scholar 

  40. Zile MR, Baicu CF, Stroud RE, Van Laer AO, Jones JA, Patel R, et al. Mechanistic relationship between MT1-MMP and the myocardial response to pressure –overload. Circ Heart Fail. 2014;7:340–50.

    Article  CAS  Google Scholar 

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The study was supported by a grant funded by National Center of Research (2011/01/B/NZ6/02661).

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Trojanek, J.B., Niemirska, A., Grzywa, R. et al. Leukocyte matrix metalloproteinase and tissue inhibitor gene expression patterns in children with primary hypertension. J Hum Hypertens 34, 355–363 (2020). https://doi.org/10.1038/s41371-019-0197-8

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