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Apoptosis at a distance: Remote activation of caspase-3 occurs early after myocardial infarction

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Abstract

Objective: After an acute myocardial infarction, the viable myocardium remote from the infarct zone is subjected to ventricular remodeling. Besides hypertrophy, processes of apoptosis may contribute to these remodeling processes. Reports on apoptosis in this area have been doubted because they were mainly based on in-situ nick-end DNA labeling (TUNEL) measurements, with questionable specifity. Moreover, the time course of initiation of these processes has not been characterized. Therefore the goals of this study were to (1) reliably determine if in the remote area of the infarcted heart apoptosis may be initiated using highly specific biochemical markers and (2) evaluate the time course of such an activation.

Methods: A well-defined model, regional myocardial infarction induced by ligation of the left anterior coronary artery in rats in vivo, was used. Heart and lung wet weights, the left ventricular end-diastolic pressure (LVEDP), and the serum level of the atrial natriuretic propeptide (proANP) were determined from 1 day up to 4 weeks as indicators of developing heart failure. In transmural biopsies from the non-ischemic left ventricular wall of the infarcted heart, the activation of caspase-3, the bcl-2/bax ratio (Western blot analysis), and the DNA laddering (LM-PCR) were determined.

Results: Although heart- and lung weights did not increase before 1 week after infarction, proANP levels were elevated already 1 day after myocardial infarction suggesting early sub-clinical heart failure. The activity of caspase-3 increased significantly to 160± 20% compared to sham operated controls as early as 1 day after ligation and remained elevated over the entire time course. In parallel, the bcl-2/bax ratio shifted toward the pro-apoptotic bax. Moreover, these clear and specific biochemical indicators of apoptosis in the remote area of the infarcted heart were paralleled by the fragmentation of genomic DNA.

Conclusion: These data demonstrate that apoptotic markers are activated in the surviving zone of the heart remote from the infarct area as early as 1 day after myocardial infarction with persistence for up to 4 weeks. This activation coincides with early markers of heart failure. The exact regulation of this apoptotic process remains to be elucidated.

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References

  1. Pfeffer MA, Braunwald E: Ventricular remodeling after myocardial infarction. Experimental observations and clinical implication. Circulation 81: 1161–1172, 1990

    PubMed  CAS  Google Scholar 

  2. Laser A, Ingwall JS, Tian R, Reis I, Hu K, Gaudron P, Ertl G, Neubauer S: Regional biochemical remodeling in non-infarcted tissue of rat heart post-myocardial infarction. J Mol Cell Cardiol 28: 1531–1538, 1996

    Article  PubMed  CAS  Google Scholar 

  3. Swynghedauw B: Molecular mechanisms of myocardial remodeling. Physiol Rev 79: 215–262, 1999

    PubMed  CAS  Google Scholar 

  4. Olivetti G, Capasso JM, Meggs LG, Sonnenblick EH, Anversa P: Cellular basis of ventricular remodeling after myocardial infarction in rats. Circ Res 68: 856–869, 1991

    PubMed  CAS  Google Scholar 

  5. Nadal-Ginard B, Kajstura J, Leri A, Anversa P: Myocyte death, growth, and regeneration in cardiac hypertrophy and heart failure. Circ Res 92: 139–150, 2003

    Article  PubMed  CAS  Google Scholar 

  6. Palojoki E, Saraste A, Eriksson A, Pulkki K, Kallajoki M, Voipio-Pulkii LM, Tikkanen I: Cardiomyocyte apoptosis adn ventricular remodeling after myocardial infarction in rats. Am J Physiol 280: H2726–H2731, 2001

    CAS  Google Scholar 

  7. Sam F, Sawyer DB, Chang DF, Eberli F, Ngoy S, Jain M, Amin Y, Apstein CS, Colucci WS: Progressive left ventricular remodeling and apoptosis late after myocardial infarction in mouse heart. Am J Physiol 279: H422–H428, 2000

    CAS  Google Scholar 

  8. Cheng W, Kajstura J, Nitahara JA, Li B, Reiss K, Liu Y, Clark WA, Krajewski S, Reed JC, Olivetti G, Anversa P: Programmed myocyte cell death affects the viable myocardium after infarction in rats. Exp Cell Res 226: 316–327, 1996

    Article  PubMed  CAS  Google Scholar 

  9. Olivetti G, Quaini F, Sala R, Lagrasta C, Corradi D, Bonacina E, Gambert SR, Cigola E, Anversa P: Acute myocardial infarction in humans is associated with activation of programmed myocyte cell death in the surviving portion of the heart. J Mol Cell Cardiol 28: 2005–2016, 1996

    PubMed  CAS  Google Scholar 

  10. James TN: Normal and abnormal consequences of apoptosis in the human heart. From postnatal morphogenesis to paroxysmal arrhythmias. Circulation 90: 556–573, 1994

    PubMed  CAS  Google Scholar 

  11. Narula J, Haider N, Virmani R, DiSalvo TG, Kolodgie FD, Hajjar RJ, Schmidt U, Semigran MJ, Dec GW, Khaw BA: Apoptosis in myocytes in end-stage heart failure. N Engl J Med 335: 1182–1189, 1996

    Article  PubMed  CAS  Google Scholar 

  12. Anversa P, Cheng W, Liu Y, Leri A, Redaelli G, Kajstura J: Apoptosis and myocardial infarction. Basic Res Cardiol 93(Suppl 3): 8–12, 1998

    PubMed  Google Scholar 

  13. Itoh G, Tamura J, Suzuki M, Suzuki Y, Koike M, Nomura M, Jie T, Ito K: DNA fragmentation of human infarcted myocardial cells demonstrated by the nick end labeling method and DNA agarose gel electrophoresis. Am J Pathol 146: 1325–1331, 1995

    PubMed  CAS  Google Scholar 

  14. Baldi A, Abbate A, Bussani R, Patti G, Melfi R, Angelini A, Dobrina A, Rossiello R, Silvestri F, Baldi F, Di Sciascio G: Apoptosis and post-infarction left ventricular remodeling. J Mol Cell Cardiol 34: 165–174, 2002

    Article  PubMed  CAS  Google Scholar 

  15. Akiyama K, Gluckman TL, Terhakopian A, Jinadasa PM, Narayan S, Singaswamy S, Massey B, Bing RJ: Apoptosis in experimental myocardial infarction in situ and in the isolated perfused heart in vitro. Tissue Cell 29: 733–743, 1997

    Article  PubMed  CAS  Google Scholar 

  16. Veinot JP, Gattinger DA, Fliss H: Early apoptosis in human myocardial infarcts. Hum Pathol 28: 485–492, 1997

    Article  PubMed  CAS  Google Scholar 

  17. Saraste A, Pulkki K, Kallajoki M, Henriksen K, Parvinen M, Voipio-Pulkki L-M: Apoptosis in human acute myocardial infarction. Circulation 95: 320–323, 1997

    PubMed  CAS  Google Scholar 

  18. Freude B, Masters TN, Kostin N, Robicsek F, Schaper J: Cardiomyocyte apoptosis in acute and chronic conditions. Basic Res Cardiol 93: 85–89, 1998

    Article  PubMed  CAS  Google Scholar 

  19. Rodriguez M, Lucchesi BR, Schaper J: Apoptosis in myocardial infarction. Ann Med 34: 470–479, 2002

    Article  PubMed  CAS  Google Scholar 

  20. Kanoh M, Takemura G, Misao J, Hayakawa K, Aoyama T, Nishigaki K, Noda T, Fujiwara T, Fukuda K, Minatoguchi S, Fujiwara H: Significance of myocytes with positive DNA in situ nick end-labeling (TUNEL) in hearts with dilated cardiomyopathy: Not apoptosis but DNA repair. Circulation 99: 2757–2764, 1999

    PubMed  CAS  Google Scholar 

  21. Ohno M, Takemura G, Ohno A, Misao J, Hayakawa Y, Minatoguchi S, Fujiwara H: Apoptotic myocytes in infarct area in rabbit hearts may be oncotic with DNA fragmentation. Analysis by electron microscopy combined with in situ nick end labeling. Circulation 98: 1422–1430, 1998

    PubMed  CAS  Google Scholar 

  22. Anversa P: Myocyte death in the pathological heart. Circ Res 86: 121–124, 2000

    PubMed  CAS  Google Scholar 

  23. Haunstetter A, Izumo S: Apoptosis: basic mechanism and implications for cardiovascular disease. Circ Res 82: 1111–1129, 1998

    PubMed  CAS  Google Scholar 

  24. Saitoh T, Nakajima M, Kawahara Y: Possible involvement of apoptotic death of myocytes in left ventricular remodeling after myocardial infarction. Jpn J Physiol 53: 247–252, 2003

    Article  PubMed  Google Scholar 

  25. Pfeffer MA, Pfeffer JM, Fishbein MC, Fletcher PJ, Spadaro J, Kloner RA, Braunwald E: Myocardial infarct size and ventricular function in rats. Circ Res 44: 503–512, 1979

    PubMed  CAS  Google Scholar 

  26. Simonis G, Honold J, Schwarz K, Braun MU, Strasser RH: Regulation of the isozymes of protein kinase C in the surviving rat myocardium after myocardial infarction: distinct modulation for PKC-alpha and PKC-delta. Basic Res Cardiol 97: 223–231, 2002

    Article  PubMed  CAS  Google Scholar 

  27. Strasser RH, Simonis G, Schön S, Braun MU, Ihl-Vahl R, Weinbrenner C, Marquetant R, Kübler W: Two distinct mechanisms mediate a differential regulation of protein kinase C isozymes in acute and prolonged myocardial ischemia. Circ Res 85: 77–87, 1999

    PubMed  CAS  Google Scholar 

  28. Schaper J, Elsässer A, Kostin N: The role of cell death in heart failure. Circ Res 85: 867–869, 1999

    PubMed  CAS  Google Scholar 

  29. Freude B, Masters TN, Robicsek F, Fokin A, Kostin S, Zimmermann R, Ullmann C, Lorenz-Meyer S, Schaper J: Apoptosis is initiated by myocardial ischemia and executed during reperfusion. J Mol Cell Cardiol 32: 197–208, 2000

    Article  PubMed  CAS  Google Scholar 

  30. Black SC, Huang JQ, Rezaiefar P, Radinovic S, Eberhart A, Nicholson DW, Rodger IW: Co-localization of the cysteine protease caspase-3 with apoptotic myocytes after in vivo myocardial ischemia and reperfusion in the rat. J Mol Cell Cardiol 30: 733–742, 1998

    Article  PubMed  CAS  Google Scholar 

  31. Yaoita H, Ogawa K, Maehara K, Maruyama Y: Inhibition of ischemia/reperfusion injury in rats by a caspase inhibitor. Circulation 97:276–281, 1998

    PubMed  CAS  Google Scholar 

  32. Okamura T, Miura T, Takemura G, Fujiwara H, Iwamoto H, Kawamura K, Kimura M, Ikeda Y, Iwatate M, Matsuzaki M: Effect of caspase inhibitors on myocardial infarct size and myocyte DNA fragmentation in the ischemia-reperfused rat heart. Cardiovasc Res 45: 642–650, 2003

    Google Scholar 

  33. Huang JQ, Radinovic S, Rezaiefar P, Black SC: In vivo myocardial infarct size reduction by a caspase inhibitor administered after the onset of ischemia. Eur J Pharmacol 402: 139–142, 2000

    Article  PubMed  CAS  Google Scholar 

  34. Condorelli G, Roncarati R, Ross J, Jr, Pisani A, Stassi G, Todaro M, Trocha S, Drusco A, Gu Y, Russo MA, Frati G, Jones SP, Lefer DJ, Napoli C, Croce CM: Heart-targeted overexpression of caspase 3 in mice increases infarct size and depresses cardiac function. Proc Natl Acad Sci 98: 9977–9982, 2001

    PubMed  CAS  Google Scholar 

  35. Kajstura J, Cheng W, Reiss K, Clark WA, Sonnenblick EH, Krajewski S, Reed JC, Anversa P: Apoptotic and necrotic myocyte death are independent contributing variables of infarct size in rats. Lab Invest 74: 86–107, 1996

    PubMed  CAS  Google Scholar 

  36. Maruyama R, Takemura G, Aoyama T, Hayakawa K, Koda M, Kawase Y: Dynamic process of apoptosis in adult rat cardiomyocytes analyzed using 48-h videomicroscopy and elecron microscopy. Am J Pathol 159: 683–691, 2001

    PubMed  CAS  Google Scholar 

  37. Black SC, Huang JQ, Rezaiefar P, Radinovic S, Eberhart A, Nicholson DW, Rodger IW: Co-localization of the cysteine protease caspase 3 with apoptotic myocytes after in vivo myocardial ischemia and reperfusion in the rat. J Mol Cell Cardiol 30: 733–742, 1998

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Clinic for Internal Medicine/Cardiology, University of Technology, Dresden, Germany

    Kerstin Schwarz, Gregor Simonis, Xinjian Yu, Stephan Wiedemann & Ruth H. Strasser

  2. Department of Internal Medicine/Cardiology, University of Technology, Fetscherstr. 76, 01307, Dresden, Germany

    Gregor Simonis

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  1. Kerstin Schwarz
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  2. Gregor Simonis
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  3. Xinjian Yu
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  4. Stephan Wiedemann
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  5. Ruth H. Strasser
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Correspondence to Gregor Simonis.

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Parts of this study were presented at the Annual Meetings of the American College of Cardiology 2002.

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Schwarz, K., Simonis, G., Yu, X. et al. Apoptosis at a distance: Remote activation of caspase-3 occurs early after myocardial infarction. Mol Cell Biochem 281, 45–54 (2006). https://doi.org/10.1007/s11010-006-0233-1

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  • DOI: https://doi.org/10.1007/s11010-006-0233-1

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