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Matrix metalloproteinase: investigation from gene to protein as effective factor in myocardial infarction

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Abstract

Current evidence indicates that extracellular matrix (ECM) remodeling is a component of acute myocardial infarction (AMI) and matrix metalloproteinase (MMP) has a role in early atherosclerosis, plaque rupture and myocardial infarction (MI). The necessity of inhibition of ECM remodeling and subsequent injuries in patients with AMI suggests that MMP might be involved in this task. Therefore, we investigated the activities of MMP-1, -2, -3, and -9 which play an important role in AMI. Plasma and peripheral blood mononuclear cells (PBMCs) of 50 patients with AMI were isolated from peripheral blood after the onset of AMI within 24 h, comparing with 50 control subjects. The active form of MMPs was measured by enzyme linked immunosorbent assay (ELISA); MMP proteins presence and expression by immunoblotting and zymography analysis; and mRNA expression of MMPs by real time reverse transcriptase polymerase chain reaction. Plasma concentrations of MMPs increase in patients rather than control subjects. Gel zymography revealed 43, 66, 45, and 83 kDa molecular weight bands which consistent with active MMP-1, -2, -3, and -9, respectively, exhibiting gelatin-degrading activity in both patient and control subjects. No up-regulation of mRNA expression was found. To our knowledge, it is the first monitoring of MMP gene and protein expression and also circulating active MMPs in Iranian patients with AMI and normal subjects. Up-regulation of MMPs activity is common in the falling myocardium and missing up-regulation of transcription indicates that protein levels of MMPs were regulated at the post transcriptional level.

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References

  1. Kim HE, Dalal SS, Young E, Legato MJ, Weisfeldt ML, D’Armiento J (2000) Disruption of the myocardial extracellular matrix leads to cardiac dysfunction. J Clin Invest 106:857–866

    Article  CAS  PubMed  Google Scholar 

  2. Woessner JF Jr (1991) Matrix metalloproteinases and their inhibitors in connective tissue remodeling. FASEB J 5:2145–2154

    CAS  PubMed  Google Scholar 

  3. Nagase H, Enghild JJ, Suzuki K, Salvesen G (1990) Stepwise activation mechanisms of the precursor of matrix metalloproteinase 3 (stromelysin) by proteinases and (4-aminophenyl)mercuric acetate. Biochemistry 29:5783–5789

    Article  CAS  PubMed  Google Scholar 

  4. Okada Y (2009) Proteinases and matrix degradation. In: Harris ED Jr, Budd RC, Genovese MC, Firestein GS, Sargent JS (eds) Kelly’s textbook of rheumatology, 8th edn. Elsevier Saunders, Philadelphia, pp 115–134

    Google Scholar 

  5. Murphy G, Cockett MI, Stephens PE, Smith BJ, Docherty AJ (1987) Stromelysin is an activator of procollagenase. A study with natural and recombinant enzymes. Biochem J 248:265–268

    CAS  PubMed  Google Scholar 

  6. Ikeda U, Shimpo M, Ohki R, Inaba H, Takahashi M, Yamamoto K, Shimada K (2000) Fluvastatin inhibits matrix metalloproteinase-1 expression in human vascular endothelial cells. Hypertension 36:325–329

    CAS  PubMed  Google Scholar 

  7. Jordan RCK, Macabeo-Ong M, Shiboski CH, Dekker N, Ginzinger DG, Wong DTW, Schmidt BL (2004) Overexpression of matrix metalloproteinase-1 and -9 mRNA is associated with progression of oral dysplasia to cancer. Clin Cancer Res 10:6460–6465

    Article  CAS  PubMed  Google Scholar 

  8. Medley TL, Kingwell BA, Gatzka CD, Pillay P, Cole TJ (2003) Matrix metalloproteinase-3 genotype contributes to age-related aortic stiffening through modulation of gene and protein expression. Circ Res 92:1254–1261

    Article  CAS  PubMed  Google Scholar 

  9. Weglarz L, Molin I, Orchel A, Parfiniewicz B, Dzierżewicz Z (2006) Quantitative analysis of the level of p53 and p21WAF1 mRNA in human colon cancer HT-29 cells treated with inositol hexaphosphate. Acta Biochim Pol 53:349–356

    CAS  PubMed  Google Scholar 

  10. Kleiner DE, Stetlerstevenson WG (1994) Quantitative zymography: detection of picogram quantities of gelatinases. Anal Biochem 218:325–329

    Article  CAS  PubMed  Google Scholar 

  11. Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680–685

    Article  CAS  PubMed  Google Scholar 

  12. Towbin H, Staehelin T, Gordon J (1979) Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci USA 76:4350–4354

    Article  CAS  PubMed  Google Scholar 

  13. Bradford M (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  CAS  PubMed  Google Scholar 

  14. Cleutjens JP, Kandala JC, Guarda E, Guntaka RV, Weber KT (1995) Regulation of collagen degradation in the rat myocardium after infarction. J Mol Cell Cardiol 27:1281–1292

    Article  CAS  PubMed  Google Scholar 

  15. Tyagi SC, Kumar SG, Haas SJ, Reddy HK, Voelker DJ, Hayden MR, Demmy TL, Schmaltz RA, Curtis JJ (1996) Post-transcriptional regulation of extracellular matrix metalloproteinase in human heart end-stage failure secondary to ischemic cardiomyopathy. J Mol Cell Cardiol 28:1415–1428

    Article  CAS  PubMed  Google Scholar 

  16. Herzog E, Gu A, Kohmoto T, Burkhoff D, Hochman JS (1998) Early activation of metalloproteinases after experimental myocardial infarction occurs in infarct and non-infarct zones. Cardiovasc Pathol 7:307–312

    Article  CAS  Google Scholar 

  17. Carlyle WC, Jacobson AW, Judd DL, Tian B, Chu C, Hauer KM, Hartman MM, McDonald KM (1997) Delayed reperfusion alters matrix metalloproteinase activity and fibronectin mRNA expression in the infarct zone of the ligated rat heart. J Mol Cell Cardiol 29:2451–2463

    Article  CAS  PubMed  Google Scholar 

  18. Sato S, Ashraf M, Millard RW, Fujiwara H, Schwartz A (1983) Connective tissue changes in early ischemia of porcine myocardium: an ultrastructural study. J Mol Cell Cardiol 15:261–275

    Article  CAS  PubMed  Google Scholar 

  19. Danielsen CC, Wiggers H, Andersen HR (1998) Increased amounts of collagenase and gelatinase in porcine myocardium following ischemia and reperfusion. J Mol Cell Cardiol 30:1431–1442

    Article  CAS  PubMed  Google Scholar 

  20. Etoh T, Joffs C, Deschamps AM, Davis J, Dowdy K, Hendrick J, Baicu S, Mukherjee R, Manhaini M, Spinale FG (2001) Myocardial and interstitial matrix metalloproteinase activity after acute myocardial infarction in pigs. Am J Physiol Heart Circ Physiol 281:H987–H994

    CAS  PubMed  Google Scholar 

  21. Kaden JJ, Dempfle CE, Sueselbeck T, Brueckmann M, Poerner TC, Haghi D, Haase KK, Borggrefe M (2003) Time-dependent changes in the plasma concentration of matrix metalloproteinase 9 after acute myocardial infarction. Cardiology 99:140–144

    Article  CAS  PubMed  Google Scholar 

  22. Lu L, Gunja-Smith Z, Woessner JF, Ursell PC, Nissen T, Galardy RE, Xu Y, Zhu P, Schwartz GG (2000) Matrix metalloproteinases and collagen ultrastructure in moderate myocardial ischemia and reperfusion in vivo. Am J Physiol Heart Circ Physiol 279:H601–H609

    CAS  PubMed  Google Scholar 

  23. Peterson JT, Li H, Dillon L, Bryant JW (2000) Evolution of matrix metalloprotease and tissue inhibitor expression during heart failure progression in the infarcted rat. Cardiovasc Res 46:307–315

    Article  CAS  PubMed  Google Scholar 

  24. Romanic AM, Burns-Kurtis CL, Gout B, Berrebi-Bertrand I, Ohlstein EH (2001) Matrix metalloproteinase expression in cardiac myocytes following myocardial infarction in the rabbit. Life Sci 68:799–814

    Article  CAS  PubMed  Google Scholar 

  25. Cheung PY, Sawicki G, Wozniak M, Wang W, Radomski MW, Schulz R (2000) Matrix metalloproteinase-2 contributes to ischemia-reperfusion injury in the heart. Circulation 101:1833–1839

    CAS  PubMed  Google Scholar 

  26. Weber KT, Sun Y, Tyagi SC, Cleutjens JP (1994) Collagen network of the myocardium: function, structural remodeling and regulatory mechanisms. J Mol Cell Cardiol 26:279–292

    Article  CAS  PubMed  Google Scholar 

  27. Rohde LE, Ducharme A, Arroyo LH, Aikawa M, Sukhova GH, Lopez-Anaya A, McClure KF, Mitchell PG, Libby P, Lee RT (1999) Matrix metalloproteinase inhibition attenuates early left ventricular enlargement after experimental myocardial infarction in mice. Circulation 99:3063–3070

    CAS  PubMed  Google Scholar 

  28. Spinale FG, Coker ML, Krombach SR, Mukherjee R, Hallak H, Houck WV, Clair MJ, Kribbs SB, Johnson LL, Peterson JT, Zile MR (1999) Matrix metalloproteinase inhibition during the development of congestive heart failure: effects on left ventricular dimensions and function. Circ Res 85:364–376

    CAS  PubMed  Google Scholar 

  29. Spinale FG, Coker ML, Bond BR, Zellner JL (2000) Myocardial matrix degradation and metalloproteinase activation in the failing heart: a potential therapeutic target. Cardiovasc Res 46:225–238

    Article  CAS  PubMed  Google Scholar 

  30. Yip D, Ahmad A, Karapetis CS, Hawkins CA, Harper PG (1999) Matrix metalloproteinase inhibitors: applications in oncology. Invest New Drugs 17:387–399

    Article  CAS  PubMed  Google Scholar 

  31. Moore G, Liao S, Curci JA, Starcher BC, Martin RL, Hendricks RT, Chen JJ, Thompson RW (1999) Suppression of experimental abdominal aortic aneurysms by systemic treatment with a hydroxamate-based matrix metalloproteinase inhibitor (RS 132908). J Vasc Surg 29:522–532

    Article  CAS  PubMed  Google Scholar 

  32. Cowan KN, Jones PL, Rabinovitch M (2000) Elastase and matrix metalloproteinase inhibitors induce regression, and tenascin-C antisense prevents progression, of vascular disease. J Clin Invest 105:21–34

    Article  CAS  PubMed  Google Scholar 

  33. Jimenez RE, Hartwig W, Antoniu BA, Compton CC, Warshaw AL, Fernandez-Del Castillo C (2000) Effect of matrix metalloproteinase inhibition on pancreatic cancer invasion and metastasis: an additive strategy for cancer control. Ann Surg 231:644–654

    Article  CAS  PubMed  Google Scholar 

  34. Escalante T, Franceschi A, Rucavado A, Gutiérrez JM (2000) Effectiveness of batimastat, a synthetic inhibitor of matrix metalloproteinases, in neutralizing local tissue damage induced by BaP1, a hemorrhagic metalloproteinase from the venom of the snake Bothrops asper. Biochem Pharmacol 60:269–274

    Article  CAS  PubMed  Google Scholar 

  35. Haq M, Shafii A, Zervos EE, Rosemurgy AS (2000) Addition of matrix metalloproteinase inhibition to conventional cytotoxic therapy reduces tumor implantation and prolongs survival in a murine model of human pancreatic cancer. Cancer Res 60:3207–3211

    CAS  PubMed  Google Scholar 

  36. Coker ML, Doscher MA, Thomas CV, Galis ZS, Spinale FG (1999) Matrix metalloproteinase synthesis and expression in isolated LV myocyte preparations. Am J Physiol 277:H777–H787

    CAS  PubMed  Google Scholar 

  37. Tyagi SC, Matsubara L, Weber KT (1993) Direct extraction and estimation of collagenase(s) activity by zymography in microquantities of rat myocardium and uterus. Clin Biochem 26:191–198

    Article  CAS  PubMed  Google Scholar 

  38. Nagase H (1997) Activation mechanisms of matrix metalloproteinases. Biol Chem 378:151–160

    CAS  PubMed  Google Scholar 

  39. Grant GM, Cobb JK, Castillo B, Klebe RJ (1996) Regulation of matrix metalloproteinases following cellular transformation. J Cell Physiol 167:177–183

    Article  CAS  PubMed  Google Scholar 

  40. Pfeffer JM, Pfeffer MA, Fletcher PJ, Braunwald E (1991) Progressive ventricular remodeling in rat with myocardial infarction. Am J Physiol 260:H1406–H1414

    CAS  PubMed  Google Scholar 

  41. Li YY, McTiernan CF, Feldman AM (2000) Interplay of matrix metalloproteinases, tissue inhibitors of metalloproteinases and their regulators in cardiac matrix remodeling. Cardiovasc Res 46:214–224

    Article  CAS  PubMed  Google Scholar 

  42. Spinale FG, Coker ML, Heung LJ, Bond BR, Gunasinghe HR, Etoh T, Goldberg AT, Zellner JL, Crumbley AJ (2000) A matrix metalloproteinase induction/activation system exists in the human left ventricular myocardium and is upregulated in heart failure. Circulation 102:1944–1949

    CAS  PubMed  Google Scholar 

  43. Siméon A, Monier F, Emonard H, Gillery P, Birembaut P, Hornebeck W, Maquart FX (1999) Expression and activation of matrix metalloproteinases in wounds: modulation by the tripeptide-copper complex glycyl-l-histidyl-l-lysine-Cu2+. J Invest Dermatol 112:957–964

    Article  PubMed  Google Scholar 

  44. Lindsey M, Wedin K, Brown MD, Keller C, Evans AJ, Smolen J, Burns AR, Rossen RD, Michael L, Entman M (2001) Matrix-dependent mechanism of neutrophil-mediated release and activation of matrix metalloproteinase 9 in myocardial ischemia/reperfusion. Circulation 103:2181–2187

    CAS  PubMed  Google Scholar 

  45. Watanabe H, Nakanishi I, Yamashita K, Hayakawa T, Okada Y (1993) Matrix metalloproteinase-9 (92 kDa gelatinase/type IV collagenase) from U937 monoblastoid cells: correlation with cellular invasion. J Cell Sci 104:991–999

    CAS  PubMed  Google Scholar 

  46. Leber TM, Balkwill FR (1998) Regulation of monocyte MMP-9 production by TNF-alpha and a tumour-derived soluble factor (MMPSF). Br J Cancer 78:724–732

    CAS  PubMed  Google Scholar 

  47. Zhang Y, McCluskey K, Fujii K, Wahl LM (1998) Differential regulation of monocyte matrix metalloproteinase and TIMP-1 production by TNF-alpha, granulocyte-macrophage CSF, and IL-1 beta through prostaglandin-dependent and -independent mechanisms. J Immunol 161:3071–3076

    CAS  PubMed  Google Scholar 

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Acknowledgment

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.

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Authors and Affiliations

  1. Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences and Health Services, Tehran, Iran

    Sayyed Mohammad Hossein Ghaderian & Reza Akbarzadeh Najar

  2. Department of Biology, Faculty of Basic Sciences, Islamic Azad University, East Tehran Branch (Ghiamdasht), Tehran, Iran

    Akram Sadat Tabatabaei Panah

  3. Department of Clinical Biochemistry, Faculty of Medicine, Shahid Beheshti University of Medical Sciences and Health Services, Tehran, Iran

    Gashin Rezaie, Azam Rezaei Farimani & Asghar Beigi Harchegani

  4. Department of Health & Community Medicine, Faculty of Medicine, Shahid Beheshti University of Medical Sciences and Health Services, Tehran, Iran

    Eznollah Azargashb

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  1. Sayyed Mohammad Hossein Ghaderian
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Correspondence to Sayyed Mohammad Hossein Ghaderian.

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Ghaderian, S.M.H., Akbarzadeh Najar, R., Tabatabaei Panah, A.S. et al. Matrix metalloproteinase: investigation from gene to protein as effective factor in myocardial infarction. J Thromb Thrombolysis 30, 404–411 (2010). https://doi.org/10.1007/s11239-010-0465-5

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