Molecular Biology Reports

, Volume 38, Issue 8, pp 4971–4977 | Cite as

Tumor necrosis factor-α: investigation of gene polymorphism and regulation of TACE–TNF-α system in patients with acute myocardial infarction

  • Sayyed Mohammad Hossein Ghaderian
  • Reza Akbarzadeh Najar
  • Akram Sadat Tabatabaei Panah


A polymorphism within tumor necrosis factor-α (TNF-α) gene promoter and contribution of TNF-α converting enzyme (TACE) have been reported to be associated with TNF-α production which may increase susceptibility to heart failure such as acute myocardial infarction (AMI). However, the relationship between this polymorphism and susceptibility to AMI and the mechanism of TACE–TNF-α system regulation has poorly been studied. Genomic DNA and peripheral blood mononuclear cells (PBMCs) of patients with AMI and control subjects was extracted. The −308 G/A TNF-α polymorphism was detected. The mRNA transcription and protein expression levels of TNF-α and TACE were analyzed by real time RT-PCR and flow cytometry respectively as well as plasma TNF-α by ELISA. The ‘A’ allele frequency of TNF-α was significantly more frequent in the patients than controls (P < 0.001). There were statistically significant differences in TNF-α and TACE mRNA and protein levels as well as circulating TNF-α in the patients. However, these levels were higher in the patients who carry ‘A’ allele. There were significant positive correlation between these mRNAs and protein expression levels (r = 0.66, P < 0.001, r = 0.78, P < 0.001 respectively). These data suggest that genetic polymorphism in TNF-α might be helpful for determining susceptibility to AMI in Iranian patients. The TACE–TNF-α system in circulating leucocytes is stimulated which these results demonstrate that in patients with AMI, TACE expression in PBMC increases with TNF-α expression and processing of TNF-α in PBMC might be regulated by TACE at transcriptional, translational, and post-translational levels in AMI.


Acute myocardial infarction Tumor necrosis factor-α TNF-α converting enzyme Polymorphism Plasma levels 



This work was funded by Shahid Beheshti University of Medical Sciences and Health Services. Our gratitude also goes to Shahid Modarress Hospital staff for helpful collaboration. We would also like to thank Dr. Eznollah Azargashb for conduct of the statistical analyses.

Conflict of interest



  1. 1.
    Ross R (1999) Atherosclerosis—an inflammatory disease. N Engl J Med 340:115–126PubMedCrossRefGoogle Scholar
  2. 2.
    Schreyer SA, Peschon JJ, LeBoeuf RC (1996) Accelerated atherosclerosis in mice lacking tumor necrosis factor receptor p55. J Biol Chem 271:26174–26178PubMedCrossRefGoogle Scholar
  3. 3.
    Valgimigli M, Ceconi C, Malagutti P, Merli E, Soukhomovskaia O, Francolini G et al (2005) Tumor necrosis factor-alpha receptor 1 is a major predictor of mortality and new-onset heart failure in patients with acute myocardial infarction: the cytokine-activation and long-term prognosis in myocardial infarction (C-ALPHA) study. Circulation 111:863–870PubMedCrossRefGoogle Scholar
  4. 4.
    Lissoni P, Pelizzoni F, Mauri O, Perego M, Pittalis S, Barni S (1992) Enhanced secretion of tumour necrosis factor in patients with myocardial infarction. Eur J Med 1:277–280PubMedGoogle Scholar
  5. 5.
    Barath P, Fishbein MC, Cao J, Berenson J, Helfant RH, Forrester JS (1990) Detection and localization of tumor necrosis factor in human atheroma. Am J Cardiol 65:297–302PubMedCrossRefGoogle Scholar
  6. 6.
    Wilson AG, Symons JA, McDowell TL, McDevitt HO, Duff GW (1997) Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proc Natl Acad Sci USA 94:3195–3199PubMedCrossRefGoogle Scholar
  7. 7.
    Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson MF et al (1997) A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Nature 385:729–733PubMedCrossRefGoogle Scholar
  8. 8.
    Black RA (2002) Tumor necrosis factor-[alpha] converting enzyme. Int J Biochem Cell B 34:1–5CrossRefGoogle Scholar
  9. 9.
    Irwin MW, Mak S, Mann DL, Qu R, Penninger JM, Yan A et al (1999) Tissue expression and immunolocalization of tumor necrosis factor-alpha in postinfarction dysfunctional myocardium. Circulation 99:1492–1498PubMedGoogle Scholar
  10. 10.
    Zhao J, Qu XF, Zhao CY, Cao FL, Zhou T, Li WM et al (2007) Effects of metoprolol treatment on a disintegrin metalloproteinase expression and extracellular matrix remodeling after myocardial infarction in rats. Chin Med J (Engl) 120:1549–1552Google Scholar
  11. 11.
    Akatsu T, Nakamura M, Satoh M, Hiramori K (2003) Increased mRNA expression of tumour necrosis factor-alpha and its converting enzyme in circulating leucocytes of patients with acute myocardial infarction. Clin Sci (Lond) 105:39–44CrossRefGoogle Scholar
  12. 12.
    Padovani JC, Pazin-Filho A, Simoes MV, Marin-Neto JA, Zago MA, Franco RF (2000) Gene polymorphisms in the TNF locus and the risk of myocardial infarction. Thromb Res 100:263–269PubMedCrossRefGoogle Scholar
  13. 13.
    Warzocha K, Ribeiro P, Bienvenu J, Roy P, Charlot C, Rigal D et al (1998) Genetic polymorphisms in the tumor necrosis factor locus influence non-Hodgkin’s lymphoma outcome. Blood 91:3574–3581PubMedGoogle Scholar
  14. 14.
    Dizon-Townson DS, Major H, Ward K (1998) A promoter mutation in the tumor necrosis factor alpha gene is not associated with preeclampsia. J Reprod Immunol 38:55–61PubMedCrossRefGoogle Scholar
  15. 15.
    Satoh M, Iwasaka J, Nakamura M, Akatsu T, Shimoda Y, Hiramori K (2004) Increased expression of tumor necrosis factor-alpha converting enzyme and tumor necrosis factor-alpha in peripheral blood mononuclear cells in patients with advanced congestive heart failure. Eur J Heart Fail 6:869–875PubMedGoogle Scholar
  16. 16.
    Hajeer AH, Hutchinson IV (2000) TNF-alpha gene polymorphism: clinical and biological implications. Microsc Res Tech 50:216–228PubMedCrossRefGoogle Scholar
  17. 17.
    Plutzky J (2001) Inflammatory pathways in atherosclerosis and acute coronary syndromes. Am J Cardiol 88:10–15CrossRefGoogle Scholar
  18. 18.
    Louis E, Franchimont D, Piron A, Gevaert Y, Schaaf-Lafontaine N, Roland S et al (1998) Tumour necrosis factor (TNF) gene polymorphism influences TNF-alpha production in lipopolysaccharide (LPS)-stimulated whole blood cell culture in healthy humans. Clin Exp Immunol 113:401–406PubMedCrossRefGoogle Scholar
  19. 19.
    Ridker PM, Rifai N, Pfeffer M, Sacks F, Lepage S, Braunwald E (2000) Elevation of tumor necrosis factor-alpha and increased risk of recurrent coronary events after myocardial infarction. Circulation 101:2149–2153PubMedGoogle Scholar
  20. 20.
    Herrmann SM, Ricard S, Nicaud V, Mallet C, Arveiler D, Evans A et al (1998) Polymorphisms of the tumour necrosis factor-alpha gene, coronary heart disease and obesity. Eur J Clin Invest 28:59–66PubMedCrossRefGoogle Scholar
  21. 21.
    Koch W, Kastrati A, Bottiger C, Mehilli J, von Beckerath N, Schomig A (2001) Interleukin-10 and tumor necrosis factor gene polymorphisms and risk of coronary artery disease and myocardial infarction. Atherosclerosis 159:137–144PubMedCrossRefGoogle Scholar
  22. 22.
    Keso T, Perola M, Laippala P, Ilveskoski E, Kunnas TA, Mikkelsson J et al (2001) Polymorphisms within the tumor necrosis factor locus and prevalence of coronary artery disease in middle-aged men. Atherosclerosis 154:691–697PubMedCrossRefGoogle Scholar
  23. 23.
    Allen RA, Lee EM, Roberts DH, Park BK, Pirmohamed M (2001) Polymorphisms in the TNF-alpha and TNF-receptor genes in patients with coronary artery disease. Eur J Clin Invest 31:843–851PubMedCrossRefGoogle Scholar
  24. 24.
    Gurevitch J, Frolkis I, Yuhas Y, Lifschitz-Mercer B, Berger E, Paz Y et al (1997) Anti-tumor necrosis factor-alpha improves myocardial recovery after ischemia and reperfusion. J Am Coll Cardiol 30:1554–1561PubMedCrossRefGoogle Scholar
  25. 25.
    Mehta JL, Nicolini FA, Donnelly WH, Nichols WW (1992) Platelet-leukocyte-endothelial interactions in coronary artery disease. Am J Cardiol 69:8–13CrossRefGoogle Scholar
  26. 26.
    Schlag G, Redl H, Hallstrom S (1991) The cell in shock: the origin of multiple organ failure. Resuscitation 21:137–180PubMedCrossRefGoogle Scholar
  27. 27.
    Grandel U, Fink L, Blum A, Heep M, Buerke M, Kraemer HJ et al (2000) Endotoxin-induced myocardial tumor necrosis factor alpha synthesis depresses contractility of isolated rat hearts: evidence for a role of sphingosine and cyclooxygenase-2-derived thromboxane production. Circulation 102:2758–2764PubMedGoogle Scholar
  28. 28.
    Peng T, Lu X, Lei M, Feng Q (2003) Endothelial nitric-oxide synthase enhances lipopolysaccharide-stimulated tumor necrosis factor-alpha expression via cAMP-mediated p38 MAPK pathway in cardiomyocytes. J Biol Chem 278:8099–8105PubMedCrossRefGoogle Scholar
  29. 29.
    Akbarzadeh Najar R, Ghaderian SM, Tabatabaei Panah AS (2010) Activation of mitogen activated protein kinases in post-infarcted patients. J Thromb Thrombolysis. doi: 10.1007/s11239-010-0526-9 [Epub ahead of print]
  30. 30.
    Chen LL, Zhu TB, Yin H, Huang J, Wang LS, Cao KJ et al (2010) Inhibition of MAPK signaling by eNOS gene transfer improves ventricular remodeling after myocardial infarction through reduction of inflammation. Mol Biol Rep 37:3067–3072PubMedCrossRefGoogle Scholar
  31. 31.
    Ghaderian SM, Akbarzadeh Najar R, Tabatabaei Panah AS, Rezaie G, Rezaei Farimani A, Beigi Harchegani A et al (2010) Matrix metalloproteinase: investigation from gene to protein as effective factor in myocardial infarction. J Thromb Thrombolysis 30:404–411PubMedCrossRefGoogle Scholar
  32. 32.
    Zhi H, Wang H, Ren L, Shi Z, Peng H, Cui L et al (2010) Functional polymorphisms of matrix metallopeptidase-9 and risk of coronary artery disease in a Chinese population. Mol Biol Rep 37:13–20PubMedCrossRefGoogle Scholar
  33. 33.
    Libby P, Ridker PM, Maseri A (2002) Inflammation and atherosclerosis. Circulation 105:1135–1143PubMedCrossRefGoogle Scholar
  34. 34.
    Moss ML, Jin SL, Milla ME, Bickett DM, Burkhart W, Carter HL et al (1997) Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha. Nature 385:733–736PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  • Sayyed Mohammad Hossein Ghaderian
    • 1
  • Reza Akbarzadeh Najar
    • 1
  • Akram Sadat Tabatabaei Panah
    • 2
  1. 1.Department of Medical Genetics, Faculty of MedicineShahid Beheshti University of Medical Sciences and Health ServicesTehranIran
  2. 2.Department of BiologyIslamic Azad UniversityTehranIran

Personalised recommendations