Impact of several proinflammatory and cell degradation factors in patients with aortic valve stenosis

Lurins,Juris; Lurina,Dace; Svirskis,Simons; Nora‑Krukle,Zaiga; Tretjakovs,Peteris; Mackevics,Vitolds; Lejnieks,Aivars; Rapisarda,Venerando; Baylon,Vincenzo

doi:10.3892/etm.2019.7254

Impact of several proinflammatory and cell degradation factors in patients with aortic valve stenosis

Authors:
- Juris Lurins
- Dace Lurina
- Simons Svirskis
- Zaiga Nora‑Krukle
- Peteris Tretjakovs
- Vitolds Mackevics
- Aivars Lejnieks
- Venerando Rapisarda
- Vincenzo Baylon
View Affiliations

Affiliations: Faculty of Medicine, Department of Internal Diseases, Riga Stradins University, Riga, LV 1007, Latvia, Latvian Maritime Medicine Centre, Riga, LV 1007, Latvia, A. Kirchenstein Institute of Microbiology and Virology, Riga Stradins University, Riga, LV 1007, Latvia, Faculty of Medicine, Department of Human Physiology and Biochemistry, Riga Stradins University, Riga, LV 1007, Latvia, Department of Clinical and Experimental Medicine, Occupational Medicine, University Hospital ‘Policlinico‑Vittorio Emanuele’, University of Catania, Catania I‑95123, Italy, Newton Lewis Institute Scientific Research‑Life Science Park, San Gwann 3000, Malta
Published online on: February 8, 2019 https://doi.org/10.3892/etm.2019.7254
Pages: 2433-2442
Copyright: © Lurins et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Aortic valve (AoV) stenosis is the third most common cardiovascular disease. The pathogenesis of AoV stenosis is associated with an inflammatory process where MMPs serve important roles. The aim of the present study was to determine the association between matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs) and inflammatory factors, and AoV stenosis at various degrees of severity compared with the control. A total of 18 patients with mild, 19 with moderate and 15 with severe AoV stenosis were included in the present stud, and 50 individuals were enrolled in the control group. The severity of stenosis was determined by echocardiography. The expression levels of chemerin, fibroblast growth factor 21, MMP‑1, ‑3, and ‑9, and TIMP‑1 and ‑3 were analyzed by ELISA. Data were analyzed using GraphPad Prism7 software. The expression levels of MMP‑1 was increased in patients with stenosis compared with the control group (P=0.0043). Distribution of the trimodal MMP‑1 values was obtained in the stenosis group and monomodal in the control group. A total of 80% of patients in the stenosis group presented significantly increased expression levels of MMP‑1 compared with the control group (P=0.0002). Expression of MMP‑1 was significantly higher in all stenosis groups compared with the control. The highest expression level of MMP‑1 appeared in patients with moderate stenosis (P<0.0001). There was no significant difference in the expression of MMP‑3, MMP‑9 and TIMP‑1 in the aortic stenosis group, compared with the control group. A positive correlation between MMP‑1 and MMP‑9 expression levels was identified (r=0.37; P=0.017). The increase of MMP‑1 was correlated with the increase of MMP‑9, but not with the level of MMP‑3. The expression levels of chemerin was significantly elevated in patients with stenosis compared with healthy patients. The highest expression levels of chemerin were determined in patients with mild (P=0.0001) and moderate (P=0.0007) stenosis and decreased with the grade of severity compared with the control group. The expression of FGF‑21 was significantly different between the control and mild (P=0.013), moderate (P=0.015) and severe stenosis (P=0.003) groups. The expression levels of FGF‑21 increased with the increase in severity grade, reaching the maximum for severe stenosis. The results of the present study indicated that the inflammatory process is predominantly occurring at the early, mild stage of stenosis and the most prominent extracellular matrix remodeling occurs in moderate stenosis (demonstrated by MMP‑1 levels). In patients with severe stenosis, the levels of MMP‑1 and chemerin (which are lower than in a case of mild or moderate stenosis) could indicate the development of calcinosis and the reduction in activity or inactivation of the inflammatory process.

View Figures

View References

1	Beckmann E, Grau JB, Sainger R, Poggio P and Ferrari G: Insights into the use of biomarkers in calcific aortic valve disease. J Heart Valve Dis. 19:441–452. 2010.PubMed/NCBI
2	Eveborn GW, Schirmer H, Heggelund G, Lunde P and Rasmussen K: The evolving epidemiology of valvular aortic stenosis. The tromsø study. Heart. 99:396–400. 2013. View Article : Google Scholar : PubMed/NCBI
3	Stewart BF, Siscovick D, Lind BK, Gardin JM, Gottdiener JS, Smith VE, Kitzman DW and Otto CM: Clinical factors associated with calcific aortic valve disease. Cardiovascular health study. J Am Coll Cardiol. 29:630–634. 1997. View Article : Google Scholar : PubMed/NCBI
4	Cosmi JE, Kort S, Tunick PA, Rosenzweig BP, Freedberg RS, Katz ES, Applebaum RM and Kronzon I: The risk of the development of aortic stenosis in patients with ‘benign’ aortic valve thickening. Arch Intern Med. 162:2345–2347. 2002. View Article : Google Scholar : PubMed/NCBI
5	Ren X: Aortic stenosis. https://emedicine.medscape.com/article/150638-overviewUpdated October 7, 2013. December 29–2013
6	Otto CM and Prendergast B: Aortic-valve stenosis-From patients at risk to severe valve obstruction. N Engl J Med. 371:744–756. 2014. View Article : Google Scholar : PubMed/NCBI
7	Lindman BR, Clavel MA, Mathieu P, Iung B, Lancellotti P, Otto CM and Pibarot P: Calcific aortic stenosis. Nat Rev Dis Primers. 3:160062016. View Article : Google Scholar
8	Kaden JJ, Dempfle CE, Grobholz R, Tran HT and Kiliç R: Sarikoç A, Brueckmann M, Vahl C, Hagl S, Haase KK and Borggrefe M: Interleukin-1 beta promotes matrix metalloproteinase expression and cell proliferation in calcific aortic valve stenosis. Atherosclerosis. 170:205–211. 2003. View Article : Google Scholar : PubMed/NCBI
9	Kaden JJ, Dempfle CE, Grobholz R, Fischer CS, Vocke DC, Kiliç R, Sarikoç A, Piñol R, Hagl S, Lang S, et al: Inflammatory regulation of extracellular matrix remodeling in calcific aortic valve stenosis. Cardiovasc Pathol. 14:80–87. 2005. View Article : Google Scholar : PubMed/NCBI
10	Kaden JJ, Dempfle CE and Kiliç R: Sarikoç A, Hagl S, Lang S, Brueckmann M and Borggrefe M: Influence of receptor activator of nuclear factor kappa B on human aortic valve myofibroblasts. Exp Mol Pathol. 78:36–40. 2005. View Article : Google Scholar : PubMed/NCBI
11	Yetkin E and Waltenberger J: Molecular and cellular mechanisms of aortic stenosis. Int J Cardiol. 135:4–13. 2009. View Article : Google Scholar : PubMed/NCBI
12	Nagase H and Woessner JF Jr: Matrix metalloproteinases. J Biol Chem. 274:21491–21494. 1999. View Article : Google Scholar : PubMed/NCBI
13	Fondard O, Detaint D, Iung B, Choqueux C, Adle-Biassette H, Jarraya M, Hvass U, Couetil JP, Henin D, Michel JB, et al: Extracellular matrix remodelling in human aortic valve disease: The role of matrix metalloproteinases and their tissue inhibitors. Eur Heart J. 26:1333–1341. 2005. View Article : Google Scholar : PubMed/NCBI
14	Heymans S, Schroen B, Vermeersch P, Milting H, Gao F, Kassner A, Gillijns H, Herijgers P, Flameng W, Carmeliet P, et al: Increased cardiac expression of tissue inhibitor of metalloproteinase-1 and tissue inhibitor of metalloproteinase-2 is related to cardiac fibrosis and dysfunction in the chronic pressure-overloaded human heart. Circulation. 112:1136–1144. 2005. View Article : Google Scholar : PubMed/NCBI
15	Papazafiropoulou A and Tentolouris N: Matrix metalloproteinases and cardiovascular diseases. Hippokratia. 13:76–82. 2009.PubMed/NCBI
16	Blankenberg S, Rupprecht HJ, Poirier O, Bickel C, Smieja M, Hafner G, Meyer J, Cambien F, Tiret L and AtheroGene Investigators: Plasma concentrations and genetic variation of matrix metalloproteinase 9 and prognosis of patients with cardiovascular disease. Circulation. 107:1579–1585. 2003. View Article : Google Scholar : PubMed/NCBI
17	Regn M, Laggerbauer B, Jentzsch C, Ramanujam D, Ahles A, Sichler S, Calzada-Wack J, Koenen RR, Braun A, Nieswandt B and Engelhardt S: Peptidase inhibitor 16 is a membrane-tethered regulator of chemerin processing in the myocardium. J Mol Cell Cardiol. 99:57–64. 2016. View Article : Google Scholar : PubMed/NCBI
18	Domouzoglou EM, Naka KK, Vlahos AP, Papafaklis MI, Michalis LK, Tsatsoulis A and Maratos-Flier E: Fibroblast growth factors in cardiovascular disease: The emerging role of FGF21. Am J Physiol Heart Circ Physiol. 309:H1029–H1038. 2015. View Article : Google Scholar : PubMed/NCBI
19	Han XY, Chen CY, Cheng G, Xie C, Yang M, Shou XL and Sun C: Serum fibroblast growth factor 21 levels are increased in atrial fibrillation patients. Cytokine. 73:176–180. 2015. View Article : Google Scholar : PubMed/NCBI
20	Planavila A, Redondo-Angulo I and Villarroya F: FGF21 and cardiac physiopathology. Front Endocrinol (Lausanne). 6:133–139. 2015. View Article : Google Scholar : PubMed/NCBI
21	Schumacher JD and Guo GL: Regulation of hepatic stellate cells and fibrogenesis by fibroblast growth factors. Biomed Res Int. 2016:83237472016. View Article : Google Scholar : PubMed/NCBI
22	Vahanian A, Alfieri O, Andreotti F, Antunes MJ, Barón-Esquivias G, Baumgartner H, Borger MA, Carrel TP, De Bonis M, et al: Guidelines on the management of valvular heart disease (version 2012): The joint task force on the management of valvular heart disease of the European society of cardiology (ESC) and the European association for cardio-thoracic surgery (EACTS). Eur Heart J. 33:2451–2496. 2012. View Article : Google Scholar : PubMed/NCBI
23	Lifshitz MS: Preanalysis. Blood collection overview. In: Henry's clinical diagnosis and management by laboratory methods, 23e. McPherson RA and Pincus MR: Elsevier Inc. (St Louis, Missouri). 24–26. 2017.PubMed/NCBI
24	Trinder P: Determination of glucose in blood using glucose oxidase with an alternative oxygen acceptor. Ann Clin Biochem. 6:24–27. 1969. View Article : Google Scholar
25	Izawa S, Okada M, Matsui H and Horita YJ: Quantitative determination of HDL cholesterol IVD. Med Pharm Sci. 37:1385–1388. 1997.
26	Benjamini Y, Krieger AM and Yekutieli D: Adaptive linear step-up procedures that control the false discovery rate. Biometrika. 93:491–507. 2006. View Article : Google Scholar
27	Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise JS, et al: Recommendations for chamber quantification. J Am Soc Echocardiogr. 18:1440–1463. 2005. View Article : Google Scholar : PubMed/NCBI
28	Solache-Berrocal G, Barral A, Martín M, Román-García P, Llosa JC, Naves-Díaz M, Cannata-Andía JB and Rodríguez I: The association of MMP1 1G>2G polymorphism with aortic valve. Rev Osteoporos Metab Miner. 8:115–120. 2016.
29	Mohty D, Pibarot P, Després JP, Côté C, Arsenault B, Cartier A, Cosnay P, Couture C and Mathieu P: Association between plasma LDL particle size, valvular accumulation of oxidized LDL, and inflammation in patients with aortic stenosis. Arterioscler Thromb Vasc Biol. 28:187–193. 2008. View Article : Google Scholar : PubMed/NCBI
30	Satta J, Oiva J, Salo T, Eriksen H, Ohtonen P, Biancari F, Juvonen TS and Soini Y: Evidence for an altered balance between matrix metalloproteinase-9 and its inhibitors in calcific aortic stenosis. Ann Thorac Surg. 76:681–688. 2003. View Article : Google Scholar : PubMed/NCBI
31	Rourke JL, Dranse HJ and Sinal CJ: Towards an integrative approach to understanding the role of chemerin in human health and disease. Obes Rev. 14:245–262. 2013. View Article : Google Scholar : PubMed/NCBI
32	Mariani F and Roncucci L: Chemerin/chemR23 axis in inflammation onset and resolution. Inflamm Res. 64:85–95. 2015. View Article : Google Scholar : PubMed/NCBI
33	Galante A, Pietroiusti A, Vellini M, Piccolo P, Possati G, De Bonis M, Grillo RL, Fontana C and Favalli C: C-reactive protein is increased in patients with degenerative aortic valvular stenosis. J Am Coll Cardiol. 38:1078–1082. 2001. View Article : Google Scholar : PubMed/NCBI
34	Ardans JA, Economou AP, Martinson JM Jr, Zhou M and Wahl LM: Oxidized low-density and high-density lipoproteins regulate the production of matrix metalloproteinase-1 and −9 by activated monocytes. J Leukoc Biol. 71:1012–1018. 2002.PubMed/NCBI
35	Death AK, Fisher EJ, McGrath KC and Yue DK: High glucose alters matrix metalloproteinase expression in two key vascular cells: Potential impact on atherosclerosis in diabetes. Atherosclerosis. 168:263–269. 2003. View Article : Google Scholar : PubMed/NCBI
36	Eickelberg O, Roth M, Mussmann R, Rüdiger JJ, Tamm M, Perruchoud AP and Block LH: Calcium channel blockers activate the interleukin-6 gene via the transcription factors NF-IL6 and NF-kappaB in primary human vascular smooth muscle cells. Circulation. 99:2276–2282. 1999. View Article : Google Scholar : PubMed/NCBI
37	Funck RC, Wilke A, Rupp H and Brilla CG: Regulation and role of myocardial collagen matrix remodeling in hypertensive heart disease. Adv Exp Med Biol. 432:35–44. 1997. View Article : Google Scholar : PubMed/NCBI