Association of matrix metalloproteinase 3 and endogenous inhibitors with inflammatory markers in mitral valve disease and calcification
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Calcific mitral valve stenosis (MVS) is a common disease characterized by extensive remodeling of the extracellular matrix via matrix metalloproteinases (MMPs). The mechanism of calcification due to extensive matrix remodeling remains unclear. In this study, we investigated the relationship between MMP-3, tissue inhibitors of metalloproteinases (TIMPs) as well as pro-inflammatory cytokines and the phenomenon of calcification in MVS. 212 patients having rheumatic mitral stenosis (RMS) and 155 healthy control subjects were recruited in the Cardiology Department of La Rabta Hospital University. Levels of MMP-3, TIMPs, IL-6 and TNF-α were measured by ELISA sandwich assay, hs-CRP was measured by immunoturbidimetry. Plasma levels of MMP-3, TIMP-1 and MMP-3/TIMP-2 ratio were lower only in RMS women in comparison to the control group. Calcification degree correlated positively with MMP-3 in women and men. In addition, calcification was correlated positively with MMP-3/TIMPs ratio in women patients. The inflammatory parameters were positively associated with extracellular matrix turnover biomarkers in men patients. In patients, the level of MMP-3 was increased in men and women with a calcification score ≥ 5. In addition, MMP-3 level predicted the occurrence of calcification. At ROC curves analysis, the cut-off MMP-3 level was in women was 9.21 ng/ml (sensitivity 51.1%, specificity 89.3%) and in men was 12.84 ng/ml (sensitivity 78.6%, specificity 77.8%). The high levels of MMP-3 and the biomarkers of inflammation contribute to valvular remodeling and calcification of the mitral valve.
KeywordsMitral valve stenosis Calcification Matrix metalloproteinases Inflammation
We thank all the personnel of Biochemistry and Cardiology departments for their collaboration throughout this study.
The study was supported by a grant from the “Ministry of High Education, Scientific Research and Technologies of Tunisia”.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
The study was approved by the Ethics Committee of Rabta Hospital and informed consent was obtained from all participants to this study. This work was carried out in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans.
- 5.Chang CJ, Hsu LA, Chiang CW, Ko YS, See LC, Shen YC, Ko YL, Kou CT, Lee YS, Pang JH (2003) Percutaneous transvenous mitral valvulotomy normalizes elevated circulating levels of tumor necrosis factor-alpha and interleukin-6 in mitral stenosis with heart failure. Am J Cardiol 91:1018–1020CrossRefGoogle Scholar
- 10.Fondard O, Detaint D, Iung B, Choqueux C, Adle-Biassette H, Jarraya M, Hvass U, Couetil JP, Henin D, Michel JB, Vahanian A, Jacob MP (2005) Extracellular matrix remodelling in human aortic valve disease: the role of matrix metalloproteinases and their tissue inhibitors. Eur Heart J 26:1333–1341CrossRefGoogle Scholar
- 18.Fukumoto Y, Shimokawa H, Ito A, Kadokami T, Yonemitsu Y, Aikawa M, Owada MK, Egashira K, Sueishi K, Nagai R, Yazaki Y, Takeshita A (1997) Inflammatory cytokines cause coronary arteriosclerosis like changes and alterations in the smooth-muscle phenotypes in pigs. J Cardiovasc Pharmacol 29:222–231CrossRefGoogle Scholar
- 25.Kwak HJ, Park MJ, Cho H, Park CM, Moon SI, Lee HC, Park IC, Kim MS, Rhee CH, Hong SI (2006) Transforming growth factor-beta1 induces tissue inhibitor of metalloproteinase-1 expression via activation of extracellular signal-regulated kinase and Sp1 in human fibrosarcoma cells. Mol Cancer Res 4:209–220CrossRefGoogle Scholar
- 27.Nadra I, Mason JC, Philippidis P, Florey O, Smythe CD, McCarthy GM, Landis RC, Haskard DO (2005) Proinflammatory activation of macrophages by basic calcium phosphate crystals via protein kinase C and MAP kinase pathways: a vicious cycle of inflammation and arterial calcification? Circ Res 96:1248–1256CrossRefGoogle Scholar
- 34.Reynolds JL, Joannides AJ, Skepper JN, McNair R, Schurgers LJ, Proudfoot D, Jahnen-Dechent W, Weissberg PL, Shanahan CM (2004) Human vascular smooth muscle cells undergo vesicle- mediated calcification in response to changes in extracellular calcium and phosphate concentrations: a potential mechanism for accelerated vascular calcification in ESRD. J Am Soc Nephrol 15:2857–2867CrossRefGoogle Scholar
- 36.Canver CC, Gregory RD, Cooler SD, Voytovich MC (2000) Association of osteopontin with calcification in human mitral valves. J Cardiovasc Surg (Torino) 41(2):171–174Google Scholar