Skip to main content
SpringerLink
Log in

Heat shock protein 72 and apoptosis indicate cardiac decompensation during early multiple organ failure in sheep

  • Experimental
  • Published:
Intensive Care Medicine Aims and scope Submit manuscript

Abstract

Objective

Inducible heat shock protein 72 (HSP 72) preserves myocardial function and prevents apoptosis. We investigated the expression and localization of HSP 72 and apoptosis in our previously described new model of multiple organ failure.

Design

Eighteen adult-instrumented sheep and three healthy controls were randomly assigned to one of three groups: (a) norfenefrine-masked hypovolemia plus endotoxemia (NMH+ENDO); (b) norfenefrine-masked hypovolemia without endotoxemia (NMH); (c) recurrent endotoxemia during normovolemia (ENDO); and (d) normovolemia without endotoxemia (CONTROLS).

Measurements and results

Hearts were analyzed by light microscopy, Western blots, immunohistochemistry, and TUNEL staining. HSP 72 expression was approximately threefold increased in NMH+ENDO compared with the other groups (p<0.05) and was localized mainly in left ventricular cardiomyocytes. HSP 72 was elevated in animals with norfenefrine-refractory shock compared to survivors (p=0.015). TUNEL-positive cells in the left ventricle were significantly elevated in the NMH+ENDO group (p=0.05) and correlated with HSP 72 expression (r=0.51, p=0.018). HSP 72 correlated positively with heart rate (r=0.76, p<0.0001), the prefinal hourly dose of norfenefrine (r=0.88, p<0.0001), and negatively with left ventricular stroke work index (r=−0.52, p=0.028). Double staining revealed TUNEL-positive cells with and without HSP 72 expression. Micronecroses were only detectable in NMH and NMH+ENDO without intergroup difference or correlations with hemodynamics.

Conclusion

HSP 72 overexpression and apoptosis, but not necrosis, indicate cardiovascular decompensation and poor outcome during early multiple organ failure.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1a,b
Fig. 2A–H
Fig. 3
Fig. 4a,b
Fig. 5A,B

Similar content being viewed by others

References

  1. Lindquist S (1986) The heat-shock response. Annu Rev Biochem 55:1151–1191

    CAS  PubMed  Google Scholar 

  2. Lindquist S, Craig EA (1988) The heat-shock proteins. Annu Rev Genet 22:631–677

    PubMed  Google Scholar 

  3. Georgopoulos C, Welch WJ (1994) Role of the major heat shock proteins as molecular chaperones. Annu Rev Cell Biol 9:601–634

    Google Scholar 

  4. Welch WJ (1987) The mammalian heat shock (or stress) response: a cellular defense mechanism. Adv Exp Med Biol 225:287–304

    CAS  PubMed  Google Scholar 

  5. Gabai VL, Meriin AB, Mosser DD, Caron AW, Rits S, Shifrin VI, Sherman MY (1997) Hsp70 prevents activation of stress kinases. A novel pathway of cellular thermotolerance. J Biol Chem 272:18033–18037

    Article  CAS  PubMed  Google Scholar 

  6. Beere HM, Wolf BB, Cain K, Mosser DD, Mahboubi A, Kuwana T, Tailor P, Morimoto RI, Cohen GM, Green DR (2000) Heat-shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome. Nat Cell Biol 2:469–475

    Google Scholar 

  7. Saleh A, Srinivasula SM, Balkir L, Robbins PD, Alnemri ES (2000) Negative regulation of the Apaf-1 apoptosome by Hsp70. Nat Cell Biol 2:476–483

    Google Scholar 

  8. Li CY, Lee JS, Ko YG, Kim JI, Seo JS (2000) Heat shock protein 70 inhibits apoptosis downstream of cytochrome c release and upstream of caspase-3 activation. J Biol Chem 275:25665–25671

    Article  CAS  PubMed  Google Scholar 

  9. Gabai VL, Mabuchi K, Mosser DD, Sherman MY (2002) Hsp72 and stress kinase c-jun N-terminal kinase regulate the bid-dependent pathway in tumor necrosis factor-induced apoptosis. Mol Cell Biol 22:3415–3424

    Article  CAS  PubMed  Google Scholar 

  10. Marber MS, Mestril R, Chi SH, Sayen MR, Yellon DM, Dillmann WH (1995) Overexpression of the rat inducible 70-kD heat stress protein in a transgenic mouse increases the resistance of the heart to ischemic injury. J Clin Invest 95:1446–1456

    PubMed  Google Scholar 

  11. Radford NB, Fina M, Benjamin IJ, Moreadith RW, Graves KH, Zhao P, Gavva S, Wiethoff A, Sherry AD, Malloy CR, Williams RS (1996) Cardioprotective effects of 70-kDa heat shock protein in transgenic mice. Proc Natl Acad Sci USA 93:2339–2342

    Article  CAS  PubMed  Google Scholar 

  12. Hutter JJ, Mestril R, Tam EK, Sievers RE, Dillmann WH, Wolfe CL (1996) Overexpression of heat shock protein 72 in transgenic mice decreases infarct size in vivo. Circulation 94:1408–1411

    CAS  PubMed  Google Scholar 

  13. Lau SS, Griffin TM, Mestril R (2000) Protection against endotoxemia by HSP70 in rodent cardiomyocytes. Am J Physiol Heart Circ Physiol 278:H1439–H1445

    CAS  PubMed  Google Scholar 

  14. Baba HA, Schmid KW, Schmid C, Blasius S, Heinecke A, Kerber S, Scheld HH, Bocker W, Deng MC (1998) Possible relationship between heat shock protein 70, cardiac hemodynamics, and survival in the early period after heart transplantation. Transplantation 65:799–804

    CAS  PubMed  Google Scholar 

  15. Hinder F, Stubbe HD, Van Aken H, Baba HA, Jahn UR, Brodner G, August C, Erren M, Booke M (2003) Early multiple organ failure after recurrent endotoxemia in the presence of vasoconstrictor-masked hypovolemia. Crit Care Med 31:903–909

    Google Scholar 

  16. Moore FA, Sauaia A, Moore EE, Haenel JB, Burch JM, Lezotte DC (1996) Postinjury multiple organ failure: a bimodal phenomenon. J Trauma 40:501–510

    CAS  PubMed  Google Scholar 

  17. Hotchkiss R, Nunnally I, Lindquist S, Taulien J, Perdrizet G, Karl I (1993) Hyperthermia protects mice against the lethal effects of endotoxin. Am J Physiol Regul Integr Comp Physiol 265:R 1447–1457

    Google Scholar 

  18. Tanonaka K, Yoshida H, Toga W, Furuhama K, Takeo S (2001) Myocardial heat shock proteins during the development of heart failure. Biochem Biophys Res Commun 283:520–525

    Article  CAS  PubMed  Google Scholar 

  19. Comini L, Gaia G, Curello S, Ceconi C, Pasini E, Benigno M, Bachetti T, Ferrari R (1996) Right heart failure chronically stimulates heat shock protein 72 in heart and liver but not in other tissues. Cardiovasc Res 31:882–890

    Article  CAS  PubMed  Google Scholar 

  20. Meng X, Brown JM, Ao L, Nordeen SK, Franklin W, Harken AH, Banerjee A (1996) Endotoxin induces cardiac HSP70 and resistance to endotoxemic myocardial depression in rats. Am J Physiol 271:C1316–C1324

    CAS  PubMed  Google Scholar 

  21. Li Z, Bing OH, Long X, Robinson KG, Lakatta EG (1997) Increased cardiomyocyte apoptosis during the transition to heart failure in the spontaneously hypertensive rat. Am J Physiol 272:H2313––H2319

    CAS  Google Scholar 

  22. Narula J, Pandey P, Arbustini E, Haider N, Narula N, Kolodgie FD, Dal Bello B, Semigran MJ, Bielsa-Masdeu A, Dec GW, Israels S, Ballester M, Virmani R, Saxena S, Kharbanda S (1999) Apoptosis in heart failure: release of cytochrome c from mitochondria and activation of caspase-3 in human cardiomyopathy. Proc Natl Acad Sci USA 96:8144–8149

    Article  CAS  Google Scholar 

  23. Meng X, Harken AH (2002) The interaction between Hsp70 and TNF-alpha expression: a novel mechanism for protection of the myocardium against post-injury depression. Shock 17:345–353

    Article  PubMed  Google Scholar 

  24. Peake SL, Pierides J, Leppard PI, Russ GR (2002) Anti-ovine interleukin-1beta monoclonal antibody immunotherapy in an ovine model of gram-negative septic shock. Crit Care Med 30:171–181

    CAS  PubMed  Google Scholar 

  25. Meldrum DR (1998) Tumor necrosis factor in the heart. Am J Physiol 274:R577–R595

    CAS  PubMed  Google Scholar 

  26. Power C, Fanning N, Redmond HP (2002) Cellular apoptosis and organ injury in sepsis: a review. Shock 18:197–211

    PubMed  Google Scholar 

  27. Jayakumar J, Suzuki K, Sammut IA, Smolenski RT, Khan M, Latif N, Abunasra H, Murtuza B, Amrani M, Yacoub MH (2001) Heat shock protein 70 gene transfection protects mitochondrial and ventricular function against ischemia-reperfusion injury. Circulation 104:I303–I307

    CAS  PubMed  Google Scholar 

  28. Christians ES, Yan LJ, Benjamin IJ (2002) Heat shock factor 1 and heat shock proteins: critical partners in protection against acute cell injury. Crit Care Med 30:S43–S50

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The excellent technical assistance of D. Möllmann, M. Wolters, and B. Schulte is gratefully acknowledged. This work has been supported in part by the IFORES Program of the University of Essen.

Author information

Authors and Affiliations

  1. Institut für Pathologie, Universität Essen, Hufelandstrasse 55, 45147, Essen, Germany

    Hideo A. Baba, Jeremias Wohlschlaeger, Florian Grabellus, Klaus J. Schmitz, Friedrich Otterbach & Kurt W. Schmid

  2. Klinik und Poliklinik für Anästhesiologie und operative Intensivmedizin, Universität Münster, Münster, Germany

    Henning D. Stubbe, Hugo Van Aken & Frank Hinder

  3. Gerhard-Domagk Institut für Pathologie, Universität Münster, Münster, Germany

    Christian August

  4. Institut für Pathophysiologie, Zentrum für Innere Medizin, Universität Essen, Essen, Germany

    Bodo Levkau

Authors
  1. Hideo A. Baba
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jeremias Wohlschlaeger
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Henning D. Stubbe
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Florian Grabellus
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hugo Van Aken
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Klaus J. Schmitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Friedrich Otterbach
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kurt W. Schmid
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Christian August
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Bodo Levkau
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Frank Hinder
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hideo A. Baba.

Additional information

H.A. Baba and J. Wohlschlaeger contributed equally to the study.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Baba, H.A., Wohlschlaeger, J., Stubbe, H.D. et al. Heat shock protein 72 and apoptosis indicate cardiac decompensation during early multiple organ failure in sheep. Intensive Care Med 30, 1405–1413 (2004). https://doi.org/10.1007/s00134-004-2161-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00134-004-2161-4

Keywords

Search

Navigation