Relationship between the Levels of MMP-9, TIMP-1, and Zinc in Biological Samples of Patients with Carotid Atherosclerosis

Zakhro A. Usmanova

Tashkent Institute of Postgraduate Medical Education;Tashkent, Uzbekistan

*Corresponding author: Zakhro A. Usmanova. Tashkent Institute of Postgraduate Medical Education; Tashkent, Uzbekistan E-mail: zahro.usmanova@yandex.ru

Published: June 25, 2015. DOI: 10.21103/Article5(2)_CR2

Abstract: 

The aim our study was to evaluate the levels of zinc in blood serum, hair, and specimens of carotid artery atherosclerotic plaques (CAAPs) and their relationship to levels of MMP-9 and TIMP-1 in the serum of patients with stable and unstable CAAPs.

Material and Methods: The study included 73 patients (55 men and 18 women) aged from 46 to 88 years (mean age 65.96±1.07 years) with CAAPs. The control group consisted of 10 healthy subjects of similar age and gender. Written informed consent was obtained from each patient. The patients were divided into two groups depending on their atherosclerotic plaque stability according to prior duplex ultrasonography. Group 1 consisted of 45 patients with stable atherosclerotic plaque, and Group 2 included 28 patients with unstable AP. Patients with hemodynamically significant carotid stenosis and unstable atherosclerotic plaques underwent carotid endarterectomy. The serum concentration of MMP-9 and TIMP-1 was determined using the standard test systems for immunoassay. Quantitative determination of the zinc level in hair and atherosclerotic plaque was carried out by optical emission spectrometry; the serum Zn was determined colorimetrically.

Results: The serum levels of MMP-9 and TIMP-1 were significantly higher in Group 2 compared to Group1 and the control group. The index of MMP-9/TIMP-1 was 1.6 times higher in Group 2 compared to the control group. The level of Zn in serum and hair was not significantly different between Groups 1 and 2.  However, Zn levels in unstable atherosclerotic plaque were lower than in the control group. Reducing the concentration of zinc in the hair was accompanied by a decrease in zinc level in atherosclerotic plaque specimens. With the progression of atherosclerosis and increasing the intima-media thickness of the common carotid artery, the level of zinc in serum and atherosclerotic plaques decreased. Increasing the serum concentration of MMP-9 was accompanied by decreasing the zinc level in atherosclerotic plaque. High serum concentration of MMP-9 and TIMP-1, and MMP-9/TIMP-1 imbalance testify to CAAP instability.

Keywords: 
carotid atherosclerosis; atherosclerotic plaque; matrix metalloproteinase-9 (MMP-9); TIMP metallopeptidase inhibitor 1; zinc.
References: 
  1. Newby AC. Metalloproteinases and vulnerable atherosclerotic plaques. Trends Cardiovasc Med 2007; 17:253–8.
  2. Gaĭgalaĭte V, Ozheraĭtene V, Kalibatene D, Laurikenas K, Sabaliauskene Z. Association between structure of atherosclerotic plaques in carotid arteries and myocardial infarction. Kardiologiia 2013; 53(9):21-5. [Article in Russian].
  3. Heo SH, Cho CH, Kim HO, Jo YH, Yoon KS, Lee JH, et al. Plaque rupture is a determinant of vascular events in carotid artery atherosclerotic disease: involvement of matrix metalloproteinases 2 and 9. J Clin Neurol 2011; 7(2):69-76.
  4. Sapienza P, di Marzo L, Borrelli V, Sterpetti AV, Mingoli A, Cresti S, et al. Metalloproteinases and their inhibitors are markers of plaque instability. Surgery 2005;37(3):355-63.
  5. Loftus IM, Naylor AR, Bell PR, Thompson MM. Plasma MMP-9 - a marker of carotid plaque instability. Eur J Vasc Endovasc Surg 2001;21(1):17-21.
  6. Eldrup N, Grønholdt ML, Sillesen H, Nordestgaard BG. Elevated matrix metalloproteinase-9 associated with stroke or cardiovascular death in patients with carotid stenosis. Circulation 2006; 114(17):1847-54.
  7. Zhou Z, Li X, Yang B, Jiang D. Relationship between lysophosphatidic acid and matrix metalloproteinase-9 plasma concentrations and carotid atheromatous plaque stability in patients with cerebral infarction. J Int Med Res 2014; 42(3):669-676.
  8. Silvello D, Narvaes LB, Albuquerque LC, Forgiarini LF, Meurer L, Martinelli NC, et al.  Serum levels and polymorphisms of matrix metalloproteinases (MMPs) in carotid artery atherosclerosis: higher MMP-9 levels are associated with plaque vulnerability. Biomarkers 2014; 19(1):49-55.
  9. Zitka O, Kukacka J, Krizkova S, Huska D, Adam V, Masarik M, et al.  Matrix metalloproteinases. Curr Med Chem 2010;17(31):3751-68.
  10. Jacobsen FE1, Lewis JA, Cohen SM. The design of inhibitors for medicinally relevant metalloproteins.  ChemMedChem 2007; 2(2):152-71.
  11. Lukacova V, Zhang Y, Mackov M, Baricic P, Raha S, Calvo JA, et al. Similarity of binding sites of human matrix metalloproteinases. J Biol Chem 2004; 279(14):14194-200. 
  12. Eby GA, Halcomb WW.  High-dose zinc to terminate angina pectoris: a review and hypothesis for action by ICAM inhibition. Med Hypotheses 2006; 66(1):169-72.
  13. Tan C, Liu Y, Li W, Deng F, Liu X, Wang X, et al. Associations of matrix metalloproteinase-9 and monocyte chemoattractant protein-1 concentrations with carotid atherosclerosis, based on measurements of plaque and intimaemedia thickness. Atherosclerosis 2014; 232(1):199-203.
  14. Alvarez B, Ruiz C, Chacón P, Alvarez-Sabin J, Matas M. Serum values of metalloproteinase-2 and metalloproteinase-9 as related to unstable plaque and inflammatory cells in patients with greater than 70% carotid artery stenosis. J Vasc Surg 2004; 40(3):469-75.
  15. Beaudeux JL, Giral P, Bruckert E, Bernard M, Foglietti MJ, Chapman MJ. Serum matrix metalloproteinase-3 and tissue inhibitor of metalloproteinases-1 as potential markers of carotid atherosclerosis in infraclinical hyperlipidemia. Atherosclerosis 2003; 169(1):139-46.
  16. Gaubatz JW, Ballantyne CM, Wasserman BA, He M, Chambless LE, Boerwinkle E, et al. Association of circulating matrix metalloproteinases with carotid artery characteristics: the Atherosclerosis Risk in Communities Carotid MRI Study. Arterioscler Thromb Vasc Biol 2010; 30(5):1034–42.
  17. Romero JR, Vasan RS, Beiser AS, Polak JF, Benjamin EJ, Wolf PA, et al. Association of carotid artery atherosclerosis with circulating biomarkers of extracellular matrix remodeling: the Framingham Offspring Study. J Stroke Cerebrovasc Dis 2008; 17(6):412-417.
  18. Golovkin AS, Matveeva VG, Grigor'ev EV, Baĭrakova IuV, Shukevich DL, Velikanova EA, et al. Postoperative dynamic changes in matrix metalloproteinase levels in patients with coronary artery bypass graft procedure complications. Kardiologiia 2012; 52(9):4-7. [Article in Russian]
  19. Kelly D, Khan SQ, Thompson M, Cockerill G, Ng LL, Samani N, et al. Plasma tissue inhibitor of metalloproteinase-1 and matrix metalloproteinase-9: novel indicators of left ventricular remodelling and prognosis after acute myocardial infarction. Eur Heart J 2008; 29(17):2116-24.
  20. Cheng M, Hashmi S, Mao X, Zeng QT. Relationships of adiponectin and matrix metalloproteinase-9 to tissue inhibitor of metalloproteinase-1 ratio with coronary plaque morphology in patients with acute coronary syndrome. Can J Cardiol 2008; 24(5):385-90.
  21. Ari E, Kaya Y, Demir H, et al. The correlation of serum trace elements and heavy metals with carotid artery atherosclerosis in maintenance hemodialysis patients. Biol Trace Elem Res 2011; 144(1-3):351-9.
  22. Beattie JH, Kwun IS. Is zinc deficiency a risk factor for atherosclerosis? Br J Nutr 2004; 91(2):177–81.
  23. Hughes S, Samman S. The effect of zinc supplementation in humans on plasma lipids, antioxidant status and thrombogenesis. J Am Coll Nutr 2006; 25(4):285–91.
  24. Vasto S, Mocchegiani E, Candore G, Listì F, Colonna-Romano G, Lio D, et al.  Inflammation, genes and zinc in ageing and age-related diseases. Biogerontology 2006; 7(5-6):315–27.
  25. Stadler N, Stanley N, Heeneman S, et al. Accumulation of zinc in human atherosclerotic lesions correlates with calcium levels but does not protect against protein oxidation. Arterioscler Thromb Vasc Biol 2008; 28(5):1024-30.
  26. Doo Sun Sim, Youngkeun Ahn. Novel inflammatory biomarkers in acute coronary syndrome. Korean J Intern Med 2013; 28(2):156-8.

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Int J Biomed. 2015; 5(2):60-64. © 2015 International Medical Research and Development Corporation. All rights reserved.