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Ischemia-reperfusion injury activates early extracellular matrix processing and expression of endostatin in the heart with differential effects of temperature

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Abstract

Acute ischemia is a well-known inductor of extracellular matrix (ECM) remodeling, which leads to the development of congestive heart failure and is associated with left ventricular dilatation. Here we investigate the timecourse of ECM processing with release of endostatin (ES) and other low-molecular-weight fragments during early ischemia-reperfusion of the heart. In this blinded study, 30 pigs were randomized to 60 min of global myocardial ischemia at either 4 or 37°C or served as control. Five transmyocardial tissue samples were collected at baseline and after ischemia within 150 min of reperfusion. Collagen XVIII cleavage products of 10–75 kDa including ES (25 kDa) were analyzed using the Western blot and ELISA method, and creatin kinase as marker of myocardial injury was determined in samples collected from the coronary sinus. We demonstrate that processing of the extracellular matrix protein collagen XVIII starts during early reperfusion, as we observed a significantly increased expression of cleavage products at 10 and 75 kDa as well as ES at 150 min of normothermic ischemia-reperfusion. We further demonstrate a differential processing of collagen XVIII depending on temperature conditions during myocardial ischemia, as an increase in cleavage products was observed after normothermic ischemia only; however, expression of ES and other fragments remained unchanged after hypothermic ischemia-reperfusion and in controls. In conclusion, this blinded study first demonstrated that processing of extracellular matrix started early after ischemia-reperfusion and depends on temperature conditions. These findings may contribute to a broader understanding of matrix processing after ischemia-reperfusion.

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References

  1. Arenas IA, Xu Y, Lopez-Jaramillo P, Davidge ST (2004) Angiotensin II-induced MMP-2 release from endothelial cells is mediated by TNF-alpha. Am J Physiol Cell Physiol 286:C779–C784

    Article  PubMed  CAS  Google Scholar 

  2. Bigg HF, Rowan AD, Barker MD, Cawston TE (2007) Activity of matrix metalloproteinase-9 against native collagen types I and III. FEBS J 274:1246–1255

    Article  PubMed  CAS  Google Scholar 

  3. Bramos D, Ikonomidis I, Tsirikos N, Kottis G, Kostopoulou V, Pamboucas C, Papadopoulou E, Venetsanou K, Giatrakos N, Yang GZ, Nihoyannopoulos P, Toumanidis S (2008) The association of coronary flow changes and inflammatory indices to ischaemia-reperfusion microvascular damage and left ventricular remodelling. Basic Res Cardiol 103:345–355

    Article  PubMed  CAS  Google Scholar 

  4. Briest W, Rassler B, Deten A, Zimmer HG (2003) Norepinephrine-induced cardiac hypertrophy and fibrosis are not due to mast cell degranulation. Mol Cell Biochem 252:229–237

    Article  PubMed  CAS  Google Scholar 

  5. Chakraborti S, Mandal M, Das S, Mandal A, Chakraborti T (2003) Regulation of matrix metalloproteinases: an overview. Mol Cell Biochem 253:269–285

    Article  PubMed  CAS  Google Scholar 

  6. Chang JH, Javier JA, Chang GY, Oliveira HB, Azar DT (2005) Functional characterization of neostatins, the MMP-derived, enzymatic cleavage products of type XVIII collagen. FEBS Lett 579:3601–3606

    Article  PubMed  CAS  Google Scholar 

  7. 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

    PubMed  CAS  Google Scholar 

  8. Deininger MH, Wybranietz WA, Graepler FT, Lauer UM, Meyermann R, Schluesener HJ (2003) Endothelial endostatin release is induced by general cell stress and modulated by the nitric oxide/cGMP pathway. FASEB J 17:1267–1276

    Article  PubMed  CAS  Google Scholar 

  9. Deschamps AM, Spinale FG (2006) Pathways of matrix metalloproteinase induction in heart failure: bioactive molecules and transcriptional regulation. Cardiovasc Res 69:666–676

    Article  PubMed  CAS  Google Scholar 

  10. Dixelius J, Larsson H, Sasaki T, Holmqvist K, Lu L, Engstrom A, Timpl R, Welsh M, Claesson-Welsh L (2000) Endostatin-induced tyrosine kinase signaling through the Shb adaptor protein regulates endothelial cell apoptosis. Blood 95:3403–3411

    PubMed  CAS  Google Scholar 

  11. Dixelius J, Cross M, Matsumoto T, Sasaki T, Timpl R, Claesson-Welsh L (2002) Endostatin regulates endothelial cell adhesion and cytoskeletal organization. Cancer Res 62:1944–1947

    PubMed  CAS  Google Scholar 

  12. Ekekezie II, Thibeault DW, Rezaiekhaligh MH, Norberg M, Mabry S, Zhang X, Truog WE (2003) Endostatin and vascular endothelial cell growth factor (VEGF) in piglet lungs: effect of inhaled nitric oxide and hyperoxia. Pediatr Res 53:440–446

    Article  PubMed  CAS  Google Scholar 

  13. Fabunmi RP, Baker AH, Murray EJ, Booth RF, Newby AC (1996) Divergent regulation by growth factors and cytokines of 95 kDa and 72 kDa gelatinases and tissue inhibitors or metalloproteinases-1, -2, and -3 in rabbit aortic smooth muscle cells. Biochem J 315(Pt 1):335–342

    PubMed  CAS  Google Scholar 

  14. Felbor U, Dreier L, Bryant RA, Ploegh HL, Olsen BR, Mothes W (2000) Secreted cathepsin L generates endostatin from collagen XVIII. EMBO J 19:1187–1194

    Article  PubMed  CAS  Google Scholar 

  15. Ferreras M, Felbor U, Lenhard T, Olsen BR, Delaisse J (2000) Generation and degradation of human endostatin proteins by various proteinases. FEBS Lett 486:247–251

    Article  PubMed  CAS  Google Scholar 

  16. Fert-Bober J, Leon H, Sawicka J, Basran RS, Devon RM, Schulz R, Sawicki G (2008) Inhibiting matrix metalloproteinase-2 reduces protein release into coronary effluent from isolated rat hearts during ischemia-reperfusion. Basic Res Cardiol 103:431–443

    Article  PubMed  CAS  Google Scholar 

  17. Heljasvaara R, Nyberg P, Luostarinen J, Parikka M, Heikkila P, Rehn M, Sorsa T, Salo T, Pihlajaniemi T (2005) Generation of biologically active endostatin fragments from human collagen XVIII by distinct matrix metalloproteases. Exp Cell Res 307:292–304

    Article  PubMed  CAS  Google Scholar 

  18. Kato T, Chang JH, Azar DT (2003) Expression of type XVIII collagen during healing of corneal incisions and keratectomy wounds. Invest Ophthalmol Vis Sci 44:78–85

    Article  PubMed  Google Scholar 

  19. King MK, Coker ML, Goldberg A, McElmurray JH 3rd, Gunasinghe HR, Mukherjee R, Zile MR, O’Neill TP, Spinale FG (2003) Selective matrix metalloproteinase inhibition with developing heart failure: effects on left ventricular function and structure. Circ Res 92:177–185

    Article  PubMed  CAS  Google Scholar 

  20. Kolkenbrock H, Ali HM, Hecker-Kia A, Buchlow G, Sorensen H, Hauer RW, Ulbrich N (1991) Characterization of a gelatinase from human rheumatoid synovial fluid cells. Eur J Clin Chem Clin Biochem 29:499–505

    PubMed  CAS  Google Scholar 

  21. Lalu MM, Pasini E, Schulze CJ, Ferrari-Vivaldi M, Ferrari-Vivaldi G, Bachetti T, Schulz R (2005) Ischaemia-reperfusion injury activates matrix metalloproteinases in the human heart. Eur Heart J 26:27–35

    Article  PubMed  CAS  Google Scholar 

  22. Li YY, Feldman AM (2001) Matrix metalloproteinases in the progression of heart failure: potential therapeutic implications. Drugs 61:1239–1252

    Article  PubMed  CAS  Google Scholar 

  23. Li YY, Feldman AM, Sun Y, McTiernan CF (1998) Differential expression of tissue inhibitors of metalloproteinases in the failing human heart. Circulation 98:1728–1734

    PubMed  CAS  Google Scholar 

  24. Lin HC, Chang JH, Jain S, Gabison EE, Kure T, Kato T, Fukai N, Azar DT (2001) Matrilysin cleavage of corneal collagen type XVIII NC1 domain and generation of a 28-kDa fragment. Invest Ophthalmol Vis Sci 42:2517–2524

    PubMed  CAS  Google Scholar 

  25. Lindsey M, Lee RT (2000) MMP inhibition as a potential therapeutic strategy for CHF. Drug News Perspect 13:350–354

    PubMed  CAS  Google Scholar 

  26. Mignatti P, Rifkin DB (1993) Biology and biochemistry of proteinases in tumor invasion. Physiol Rev 73:161–195

    PubMed  CAS  Google Scholar 

  27. O’Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J (1997) Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88:277–285

    Article  PubMed  Google Scholar 

  28. Paddenberg R, Faulhammer P, Goldenberg A, Kummer W (2006) Hypoxia-induced increase of endostatin in murine aorta and lung. Histochem Cell Biol 125:497–508

    Article  PubMed  CAS  Google Scholar 

  29. Ross RS, Borg TK (2001) Integrins and the myocardium. Circ Res 88:1112–1119

    Article  PubMed  CAS  Google Scholar 

  30. Saarela J, Rehn M, Oikarinen A, Autio-Harmainen H, Pihlajaniemi T (1998) The short and long forms of type XVIII collagen show clear tissue specificities in their expression and location in basement membrane zones in humans. Am J Pathol 153:611–626

    PubMed  CAS  Google Scholar 

  31. Saarela J, Ylikarppa R, Rehn M, Purmonen S, Pihlajaniemi T (1998) Complete primary structure of two variant forms of human type XVIII collagen and tissue-specific differences in the expression of the corresponding transcripts. Matrix Biol 16:319–328

    Article  PubMed  CAS  Google Scholar 

  32. Sasaki T, Fukai N, Mann K, Gohring W, Olsen BR, Timpl R (1998) Structure, function and tissue forms of the C-terminal globular domain of collagen XVIII containing the angiogenesis inhibitor endostatin. Embo J 17:4249–4256

    Article  PubMed  CAS  Google Scholar 

  33. Schmidt A, Addicks K, Bloch W (2004) Opposite effects of endostatin on different endothelial cells. Cancer Biol Ther 3:1162–1166 (discussion 1167–1168)

    Article  PubMed  CAS  Google Scholar 

  34. Schmidt A, Wenzel D, Ferring I, Kazemi S, Sasaki T, Hescheler J, Timpl R, Addicks K, Fleischmann BK, Bloch W (2004) Influence of endostatin on embryonic vasculo- and angiogenesis. Dev Dyn 230:468–480

    Article  PubMed  CAS  Google Scholar 

  35. Seal JB, Gewertz BL (2005) Vascular dysfunction in ischemia-reperfusion injury. Ann Vasc Surg 19:572–584

    Article  PubMed  Google Scholar 

  36. Shichiri M, Hirata Y (2001) Antiangiogenesis signals by endostatin. Faseb J 15:1044–1053

    Article  PubMed  CAS  Google Scholar 

  37. Spinale FG (2002) Matrix metalloproteinases: regulation and dysregulation in the failing heart. Circ Res 90:520–530

    Article  PubMed  CAS  Google Scholar 

  38. Spinale FG (2007) Myocardial matrix remodeling and the matrix metalloproteinases: influence on cardiac form and function. Physiol Rev 87:1285–1342

    Article  PubMed  CAS  Google Scholar 

  39. Spinale FG, Coker ML, Thomas CV, Walker JD, Mukherjee R, Hebbar L (1998) Time-dependent changes in matrix metalloproteinase activity and expression during the progression of congestive heart failure: relation to ventricular and myocyte function. Circ Res 82:482–495

    PubMed  CAS  Google Scholar 

  40. Suhr F, Brixius K, de Marees M, Bolck B, Kleinoder H, Achtzehn S, Bloch W, Mester J (2007) Effects of short-term vibration and hypoxia during high-intensity cycling exercise on circulating levels of angiogenic regulators in humans. J Appl Physiol 103:474–483

    Article  PubMed  CAS  Google Scholar 

  41. Urbich C, Reissner A, Chavakis E, Dernbach E, Haendeler J, Fleming I, Zeiher AM, Kaszkin M, Dimmeler S (2002) Dephosphorylation of endothelial nitric oxide synthase contributes to the anti-angiogenic effects of endostatin. FASEB J 16:706–708

    PubMed  CAS  Google Scholar 

  42. Van Wart HE, Birkedal-Hansen H (1990) The cysteine switch: a principle of regulation of metalloproteinase activity with potential applicability to the entire matrix metalloproteinase gene family. Proc Natl Acad Sci USA 87:5578–5582

    Article  PubMed  Google Scholar 

  43. Wen W, Moses MA, Wiederschain D, Arbiser JL, Folkman J (1999) The generation of endostatin is mediated by elastase. Cancer Res 59:6052–6056

    PubMed  CAS  Google Scholar 

  44. Wenzel D, Schmidt A, Reimann K, Hescheler J, Pfitzer G, Bloch W, Fleischmann BK (2006) Endostatin, the proteolytic fragment of collagen XVIII, induces vasorelaxation. Circ Res 98:1203–1211

    Article  PubMed  CAS  Google Scholar 

  45. Wu M (2005) Endothelial focal adhesions and barrier function. J Physiol 569:359–366

    Article  PubMed  CAS  Google Scholar 

  46. Yamaguchi N, Anand-Apte B, Lee M, Sasaki T, Fukai N, Shapiro R, Que I, Lowik C, Timpl R, Olsen BR (1999) Endostatin inhibits VEGF-induced endothelial cell migration and tumor growth independently of zinc binding. EMBO J 18:4414–4423

    Article  PubMed  CAS  Google Scholar 

  47. Yasumitsu H, Miyazaki K, Umenishi F, Koshikawa N, Umeda M (1992) Comparison of extracellular matrix-degrading activities between 64-kDa and 90-kDa gelatinases purified in inhibitor-free forms from human schwannoma cells. J Biochem 111:74–80

    PubMed  CAS  Google Scholar 

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Acknowledgments

This study was supported by the Koeln Fortune Program, Faculty of Medicine, University of Cologne. We thank Mojgan Ghilav and Anika Voß, Institute of Cardiovascular Research and Sports Medicine, German Sports University Cologne, for expert technical assistance and support during protein analysis.

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Authors and Affiliations

  1. Department of Internal Medicine I (Cardiology, Angiology, Pneumology), Friedrich-Schiller University, Erlanger Allee 101, 07740, Jena, Germany

    Alexander Lauten & Hans R. Figulla

  2. Department of Cardiothoracic Surgery, University Hospital Cologne, Kerpener Str. 62, 50937, Cologne, Germany

    Ewa Majos, Andre Mühlich & Thorsten Wahlers

  3. Institute for Experimental Medicine, University of Cologne, Cologne, Germany

    Sebastian Weider & Wilhelm Bloch

  4. Institute of Cardiovascular Research and Sports Medicine, German Sports University Cologne, Cologne, Germany

    Jürgen H. Fischer

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  1. Alexander Lauten
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Correspondence to Alexander Lauten.

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Lauten, A., Majos, E., Mühlich, A. et al. Ischemia-reperfusion injury activates early extracellular matrix processing and expression of endostatin in the heart with differential effects of temperature. Basic Res Cardiol 104, 559–569 (2009). https://doi.org/10.1007/s00395-009-0013-7

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  • DOI: https://doi.org/10.1007/s00395-009-0013-7

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