American Journal of Cardiology
Volume 101, Issue 11, Supplement , Pages S63-S68 , 2 June 2008

Amino Acid Supplementation Differentially Modulates STAT1 and STAT3 Activation in the Myocardium Exposed to Ischemia/Reperfusion Injury

  • Tiziano M. Scarabelli, MD, PhD

      Affiliations

    • Center for Heart and Vessel Preclinical Studies, St. John Hospital and Medical Center, Wayne State University School of Medicine, Detroit, Michigan, USA
    • ,
  • Paul A. Townsend, PhD

      Affiliations

    • Department of Human Genetics, University of Southampton, Southampton, England
    • ,
  • Carol Chen Scarabelli, MSc

      Affiliations

    • Division of Cardiology, VA Ann Arbor Health Care System, University of Michigan, Ann Arbor, Michigan, USA
    • ,
  • Zhaokan Yuan, PhD

      Affiliations

    • Center for Heart and Vessel Preclinical Studies, St. John Hospital and Medical Center, Wayne State University School of Medicine, Detroit, Michigan, USA
    • ,
  • Roy B. McCauley, PhD

      Affiliations

    • Center for Heart and Vessel Preclinical Studies, St. John Hospital and Medical Center, Wayne State University School of Medicine, Detroit, Michigan, USA
    • ,
  • Justin Di Rezze, PhD

      Affiliations

    • Center for Heart and Vessel Preclinical Studies, St. John Hospital and Medical Center, Wayne State University School of Medicine, Detroit, Michigan, USA
    • ,
  • David Patel, BSc

      Affiliations

    • Center for Heart and Vessel Preclinical Studies, St. John Hospital and Medical Center, Wayne State University School of Medicine, Detroit, Michigan, USA
    • ,
  • Jeff Putt, BSc

      Affiliations

    • Center for Heart and Vessel Preclinical Studies, St. John Hospital and Medical Center, Wayne State University School of Medicine, Detroit, Michigan, USA
    • ,
  • Zuhair Allebban, PhD

      Affiliations

    • Center for Heart and Vessel Preclinical Studies, St. John Hospital and Medical Center, Wayne State University School of Medicine, Detroit, Michigan, USA
    • ,
  • John Abboud, MD

      Affiliations

    • Center for Heart and Vessel Preclinical Studies, St. John Hospital and Medical Center, Wayne State University School of Medicine, Detroit, Michigan, USA
    • ,
  • Karuna Chilukuri, PhD

      Affiliations

    • Center for Heart and Vessel Preclinical Studies, St. John Hospital and Medical Center, Wayne State University School of Medicine, Detroit, Michigan, USA
    • ,
  • Julius Gardin, MD

      Affiliations

    • Center for Heart and Vessel Preclinical Studies, St. John Hospital and Medical Center, Wayne State University School of Medicine, Detroit, Michigan, USA
    • ,
  • Louis Saravolatz, MD

      Affiliations

    • Center for Heart and Vessel Preclinical Studies, St. John Hospital and Medical Center, Wayne State University School of Medicine, Detroit, Michigan, USA
    • ,
  • Richard A. Knight, MD, PhD

      Affiliations

    • Medical Molecular Biology Unit, Institute of Child Health, University College London, London, England.
    • ,
  • David S. Latchman, PhD

      Affiliations

    • Medical Molecular Biology Unit, Institute of Child Health, University College London, London, England.
    • ,
  • Anastasis Stephanou, PhD

      Affiliations

    • Medical Molecular Biology Unit, Institute of Child Health, University College London, London, England.
    • Corresponding Author InformationAddress for reprints: Anastasis Stephanou, PhD, Medical Molecular Biology Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, England.

References 

  1. Olivetti G, Quani F, Sala R, Lagrasta C, Corradi D, Bonacina E, et al. Acute myocardial infarction in humans is associated with the activation of programmed myocyte cell death in the surviving portion of the heart. J Mol Cell Cardiol. 1994;28:2005–2016
  2. Stephanou A, Brar BK, Scarabelli T, Knight RA, Latchman DS. Distinct initiator caspases are required for the induction of apoptosis in cardiac myocytes in ischaemia versus reperfusion injury. Cell Death Differ. 2001;8:434–435
  3. Scarabelli TM, Stephanou A, Pasini E, Comini L, Raddino R, Knight RA, et al. Different signalling pathways induce apoptosis in endothelial cells and cardiac myocytes during ischaemia/reperfusion injury. Circ Res. 2002;90:745–748
  4. Jeremias I, Kupatt C, Martin-Villalba A, Habazettl H, Schenkel J, Boekstegers P, et al. Involvement of CD95/Apo1/Fas in cell death after myocardial ischaemia. Circulation. 2000;102:915–920
  5. Stephanou A, Latchman DS. Opposing actions of STAT-1 and STAT-3. Growth Factors. 2005;23:177–182
  6. Kumar A, Commane M, Flickinger TW, Horvath CM, Stark GR. Defective TNF-α-induced apoptosis in STAT1-null cells due to low constitutive levels of caspases. Science. 1997;278:1630–1632
  7. Stephanou A, Brar BK, Scarabelli T, Jonassen AK, Yellon DM, Marber MS, et al. Ischaemia-induced STAT-1 expression and activation plays a critical role in cardiac myocyte apoptosis. J Biol Chem. 2000;275:10002–10008
  8. Stephanou A, Scarabelli T, Brar BK, Nakanishi Y, Matsumura M, Knight RA, et al. Induction of apoptosis and Fas/FasL expression by ischaemia/reperfusion in cardiac myocytes requires serine 727 of the STAT1 but not tyrosine 701. J Biol Chem. 2001;276:28340–28347
  9. Stephanou A, Brar BK, Knight RA, Latchman DS. Opposing actions of STAT-1 and STAT-3 on the Bcl-2 and Bcl-x promoters. Cell Death Differ. 2000;7:329–330
  10. Stephanou A, Scarabelli T, Townsend PA, Bell R, Yellon DM, Knight RA, et al. The carboxyl-terminal activation domain of the STAT-1 transcription factor enhances ischaemia/reperfusion-induced apoptosis in cardiac myocytes. FASEB J. 2002;16:1841–1843
  11. Stephanou A. Activated STAT-1 pathway in the myocardium as a novel therapeutic target in ischaemia/reperfusion injury. Eur Cytokine Netw. 2002;13:401–403
  12. Menegazzi M, Tedeschi E, Dussin D, De Prati AC, Cavalieri E, Mariotto S, et al. Anti-interferon γ action of epigallocatechin-3-gallate mediated by specific inhibition of STAT1 activation. FASEB J. 2001;15:1309–1311
  13. Townsend PA, Scarabelli TM, Pasini E, Gitti G, Menegazzi M, Suzuki H, et al. Epigallocatechin-3-gallate inhibits STAT-1 activation and protects cardiac myocytes from ischemia/reperfusion–induced apoptosis. FASEB J. 2004;18:1621–1623
  14. Khan N, Afaq F, Saleem M, Ahmad N, Mukhtar H. Targeting multiple signaling pathways by green tea polyphenol (-)-epigallocatechin-3-gallate. Cancer Res. 2006;66:2500–2505
  15. McCormick J, Barry SP, Sivarajah A, Stefanutti G, Townsend PA, Lawrence KM, et al. Free radical scavenging inhibits STAT phosphorylation following in vivo ischemia/reperfusion injury. FASEB J. 2006;20:2115–2117
  16. Scarabelli TM, Pasini E, Stephanou A, Chen-Scarabelli C, Knight RA, Latchman DS, et al. Nutritional supplementation with mixed essential amino acids enhances myocyte survival, preserving mitochondrial functional capacity during ischemia-reperfusion injury. Am J Cardiol. 2004;93:35–40
  17. Hilfiker-Kleiner D, Hilfiker A, Fuchs M, Kaminski K, Schaefer A, Schieffer B, et al Signal transducer and activator of transcription 3 is required for myocardial capillary growth, control of interstitial matrix deposition, and heart protection from ischemic injury. Circ Res. 2004;95:187–195
  18. Harada M, Qin Y, Takano H, Minamino T, Zou Y, Toko H, et al G-CSF prevents cardiac remodelling after myocardial infarction by activating the JAK-STAT pathway in cardiomyocytes. Nat Med. 2005;11:305–311
  19. Norton LE, Layman DK. Leucine regulates translation initiation of protein synthesis in skeletal muscle after exercise. J Nutr. 2006;136:533–537
  20. Proud CG. Ras, PI3-kinase and mTOR signaling in cardiac hypertrophy. Cardiovasc Res. 2004;63:403–413
  21. Fang P, Hwa V, Rosenfeld RG. Interferon-γ-induced dephosphorylation of STAT3 and apoptosis are dependent on the mTOR pathway. Exp Cell Res. 2006;312:1229–1239

 This work was supported by the St. John Guild Foundation and the British Heart Foundation.

 Statement of author disclosure: Please see the Author Disclosures section at the end of this article.

PII: S0002-9149(08)00398-6

doi: 10.1016/j.amjcard.2008.03.003

American Journal of Cardiology
Volume 101, Issue 11, Supplement , Pages S63-S68 , 2 June 2008

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