Cell Stress and Chaperones

, Volume 13, Issue 2, pp 199–206

Interaction of serum 70-kDa heat shock protein levels and HspA1B (+1267) gene polymorphism with disease severity in patients with chronic heart failure

  • Tímea Gombos
  • Zsolt Förhécz
  • Zoltán Pozsonyi
  • Lívia Jánoskuti
  • Zoltán Prohászka
Original Paper



Circulating heat shock protein 70 (Hsp70) is present in the circulation of healthy individuals and in patients with various disorders, including chronic heart failure (CHF). However, the source and routes of release of Hsp70 is only partially characterised in clinical samples.


The purpose of this study was to study the clinical and biological correlates of Hsp70 in a CHF population and, for the first time, to investigate the association of HspA1B (also known as Hsp70-2) +1267 alleles with serum Hsp70 levels.


A total of 167 patients (123 men, 44 women) with <45% left ventricular ejection fraction (LVEF) were enrolled; serum Hsp70 level was determined by enzyme-linked immunosorbent assay and HspA1B +1267 polymorphism by polymerase chain reaction–restriction fragment length polymorphism.


Increased Hsp70 levels were present in patients with severe CHF (NYHA III–IV) as compared to the group of NYHA I–II (p = 0.003). Hsp70 levels correlated with LVEF, NT-proBNP, serum bilirubin, aspartate aminotransferase, alanine aminotransferase, γGT (p < 0.05) concentrations in patients with severe CHF, although no correlation was observed between Hsp70 and CRP, TNF-α, or IL-6. HspA1B allele G was associated with higher Hsp70 levels (p = 0.001) in patients in NYHA IV class as compared to carriers of allele A.


Serum Hsp70 levels were associated with disease severity in heart failure patients. An interaction with the presence of HspA1B +1267 allele G was observed for Hsp70 concentrations. Hsp70 correlates with markers of heart function and hepatic injury, but not with signs of inflammation.


Heart failure Inflammation Liver Stress proteins 



chronic heart failure


heat shock protein


acute myocardial infarction

HELLP syndrome

haemolytic anemia elevated liver enzymes low platelet count


tumour necrosis factor




ejection fraction


body mass index


N-terminal pro-brain natriuretic peptide


New York Heart Association


aspartate aminotransferase


alanine aminotransferase


gamma-glutamyl transpeptidase


C-reactive protein


red blood cell count


non-insulin-dependent diabetes mellitus


  1. Asea A, Kraeft SK, Kurt-Jones EA et al (2000) HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat Med 6:435–442PubMedCrossRefGoogle Scholar
  2. Balog A, Gyulai Z, Boros LG, Farkas G, Takacs T, Lonovics J, Mandi Y (2005) Polymorphism of the TNF-alpha, HSP70-2, and CD14 genes increases susceptibility to severe acute pancreatitis. Pancreas 30:e46–e50PubMedCrossRefGoogle Scholar
  3. Basu S, Binder RJ, Suto R, Anderson KM, Srivastava PK (2000) Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activate the NF-kappa B pathway. Int Immunol 12:1539–1546PubMedCrossRefGoogle Scholar
  4. Bausero MA, Gastpar R, Multhoff G, Asea A (2005) Alternative mechanism by which IFN-gamma enhances tumor recognition: active release of heat shock protein 72. J Immunol 175:2900–2912PubMedGoogle Scholar
  5. Chouchane L, Ahmed SB, Baccouche S, Remadi S (1997) Polymorphism in the tumor necrosis factor-alpha promotor region and in the heat shock protein 70 genes associated with malignant tumors. Cancer 80:1489–1496PubMedCrossRefGoogle Scholar
  6. Dhingra R, Larson MG, Benjamin EJ et al (2006) Cross-sectional correlates of serum heat shock protein 70 in the community. Am J Hypertens 19:227–231, discussion 232–223PubMedCrossRefGoogle Scholar
  7. Dybdahl B, Wahba A, Lien E et al (2002) Inflammatory response after open heart surgery: release of heat-shock protein 70 and signaling through toll-like receptor-4. Circulation 105:685–690PubMedCrossRefGoogle Scholar
  8. Dybdahl B, Slordahl SA, Waage A, Kierulf P, Espevik T, Sundan A (2005) Myocardial ischaemia and the inflammatory response: release of heat shock protein 70 after myocardial infarction. Heart 91:299–304PubMedCrossRefGoogle Scholar
  9. Febbraio MA, Ott P, Nielsen HB et al (2002) Exercise induces hepatosplanchnic release of heat shock protein 72 in humans. J Physiol 544:957–962PubMedCrossRefGoogle Scholar
  10. Fehrenbach E, Niess AM, Voelker K, Northoff H, Mooren FC (2005) Exercise intensity and duration affect blood soluble HSP72. Int J Sports Med 26:552–557PubMedCrossRefGoogle Scholar
  11. Flohe SB, Bangen JM, Flohe S, Agrawal H, Bergmann K, Schade FU (2007) Origin of immunomodulation after soft tissue trauma: potential involvement of extracellular heat-shock proteins. Shock 27:494–502PubMedCrossRefGoogle Scholar
  12. Galley HF, Lowe PR (2003) Fishing in the gene pool. Crit Care Med 31:317–318PubMedCrossRefGoogle Scholar
  13. Genth-Zotz S, Bolger AP, Kalra PR et al (2004) Heat shock protein 70 in patients with chronic heart failure: relation to disease severity and survival. Int J Cardiol 96:397–401PubMedCrossRefGoogle Scholar
  14. Giacconi R, Caruso C, Lio D et al (2005) 1267 HSP70-2 polymorphism as a risk factor for carotid plaque rupture and cerebral ischaemia in old type 2 diabetes-atherosclerotic patients. Mech Ageing Dev 126:866–873PubMedCrossRefGoogle Scholar
  15. Giacconi R, Cipriano C, Muti E et al (2006) Involvement of -308 TNF-alpha and 1267 Hsp70-2 polymorphisms and zinc status in the susceptibility of coronary artery disease (CAD) in old patients. Biogerontology 7:347–356PubMedCrossRefGoogle Scholar
  16. Giannessi D, Colotti C, Maltinti M et al (2007) Circulating heat shock proteins and inflammatory markers in patients with idiopathic left ventricular dysfunction: their relationships with myocardial and microvascular impairment. Cell Stress Chaperones 12:265–274PubMedCrossRefGoogle Scholar
  17. Kannel WB (2000) Incidence and epidemiology of heart failure. Heart Fail Rev 5:167–173PubMedCrossRefGoogle Scholar
  18. Klausz G, Molnar T, Nagy F, Gyulai Z, Boda K, Lonovics J, Mandi Y (2005) Polymorphism of the heat-shock protein gene Hsp70-2, but not polymorphisms of the IL-10 and CD14 genes, is associated with the outcome of Crohn’s disease. Scand J Gastroenterol 40:1197–1204PubMedCrossRefGoogle Scholar
  19. Knowlton AA, Eberli FR, Brecher P, Romo GM, Owen A, Apstein CS (1991) A single myocardial stretch or decreased systolic fiber shortening stimulates the expression of heat shock protein 70 in the isolated, erythrocyte-perfused rabbit heart. J Clin Invest 88:2018–2025PubMedCrossRefGoogle Scholar
  20. Mestiri S, Bouaouina N, Ahmed SB, Khedhaier A, Jrad BB, Remadi S, Chouchane L (2001) Genetic variation in the tumor necrosis factor-alpha promoter region and in the stress protein hsp70-2: susceptibility and prognostic implications in breast carcinoma. Cancer 91:672–678PubMedCrossRefGoogle Scholar
  21. Milner CM, Campbell RD (1990) Structure and expression of the three MHC-linked HSP70 genes. Immunogenetics 32:242–251PubMedCrossRefGoogle Scholar
  22. Molvarec A, Prohaszka Z, Nagy B, Szalay J, Fust G, Karadi I, Rigo J Jr (2006) Association of elevated serum heat-shock protein 70 concentration with transient hypertension of pregnancy, preeclampsia and superimposed preeclampsia: a case-control study. J Hum Hypertens 20:780–786PubMedCrossRefGoogle Scholar
  23. Molvarec A, Prohaszka Z, Nagy B et al (2007) Association of increased serum heat shock protein 70 and C-reactive protein concentrations and decreased serum alpha(2)-HS glycoprotein concentration with the syndrome of hemolysis, elevated liver enzymes, and low platelet count. J Reprod Immunol 73:172–179PubMedCrossRefGoogle Scholar
  24. Pittet JF, Lee H, Morabito D, Howard MB, Welch WJ, Mackersie RC (2002) Serum levels of Hsp 72 measured early after trauma correlate with survival. J Trauma 52:611–617, discussion 617PubMedCrossRefGoogle Scholar
  25. Pociot F, Ronningen KS, Nerup J (1993) Polymorphic analysis of the human MHC-linked heat shock protein 70 (HSP70-2) and HSP70-Hom genes in insulin-dependent diabetes mellitus (IDDM). Scand J Immunol 38:491–495PubMedCrossRefGoogle Scholar
  26. Pockley AG, Shepherd J, Corton JM (1998) Detection of heat shock protein 70 (Hsp70) and anti-Hsp70 antibodies in the serum of normal individuals. Immunol Invest 27:367–377PubMedCrossRefGoogle Scholar
  27. Prohaszka Z, Fust G (2004) Immunological aspects of heat-shock proteins—the optimum stress of life. Mol Immunol 41:29–44PubMedCrossRefGoogle Scholar
  28. Prohaszka Z, Singh M, Nagy K, Kiss E, Lakos G, Duba J, Fust G (2002) Heat shock protein 70 is a potent activator of the human complement system. Cell Stress Chaperones 7:17–22PubMedCrossRefGoogle Scholar
  29. Satoh M, Shimoda Y, Akatsu T, Ishikawa Y, Minami Y, Nakamura M (2006) Elevated circulating levels of heat shock protein 70 are related to systemic inflammatory reaction through monocyte Toll signal in patients with heart failure after acute myocardial infarction. Eur J Heart Fail 8:810–815PubMedCrossRefGoogle Scholar
  30. Schroeder S, Reck M, Lehmann LE, Book M, Hoeft A, Stuber F (2000) The Pstl polymorphism of the endotoxin-inducible heat-shock protein 70-2 gene does not affect messenger RNA level in human whole-blood cultures. Intensive Care Med 26:1139–1143PubMedCrossRefGoogle Scholar
  31. Stewart S, MacIntyre K, Hole DJ, Capewell S, McMurray JJ (2001) More ‘malignant’ than cancer? Five-year survival following a first admission for heart failure. Eur J Heart Fail 3:315–322PubMedCrossRefGoogle Scholar
  32. Stewart S, MacIntyre K, Capewell S, McMurray JJ (2003) Heart failure and the aging population: an increasing burden in the 21st century? Heart 89:49–53PubMedCrossRefGoogle Scholar
  33. St Rammos K, Koullias GJ, Hassan MO, Argyrakis NP, Voucharas CG, Scarupa SJ, Cowte TG (2002) Low preoperative HSP70 atrial myocardial levels correlate significantly with high incidence of postoperative atrial fibrillation after cardiac surgery. Cardiovasc Surg 10:228–232PubMedCrossRefGoogle Scholar
  34. Tavaria M, Gabriele T, Kola I, Anderson RL (1996) A hitchhiker’s guide to the human Hsp70 family. Cell Stress Chaperones 1:23–28PubMedCrossRefGoogle Scholar
  35. Trost SU, Omens JH, Karlon WJ, Meyer M, Mestril R, Covell JW, Dillmann WH (1998) Protection against myocardial dysfunction after a brief ischemic period in transgenic mice expressing inducible heat shock protein 70. J Clin Invest 101:855–862PubMedCrossRefGoogle Scholar
  36. Vargas-Alarcon G, Londono JD, Hernandez-Pacheco G et al (2002) Heat shock protein 70 gene polymorphisms in Mexican patients with spondyloarthropathies. Ann Rheum Dis 61:48–51PubMedCrossRefGoogle Scholar
  37. Wright BH, Corton JM, El-Nahas AM, Wood RF, Pockley AG (2000) Elevated levels of circulating heat shock protein 70 (Hsp70) in peripheral and renal vascular disease. Heart Vessels 15:18–22PubMedCrossRefGoogle Scholar
  38. Zhao Y, Wang W, Qian L (2007) Hsp70 may protect cardiomyocytes from stress-induced injury by inhibiting Fas-mediated apoptosis. Cell Stress Chaperones 12:83–95PubMedCrossRefGoogle Scholar
  39. Zhou F, Wang F, Li F et al (2005) Association of hsp70-2 and hsp-hom gene polymorphisms with risk of acute high-altitude illness in a Chinese population. Cell Stress Chaperones 10:349–356PubMedCrossRefGoogle Scholar

Copyright information

© Cell Stress Society International 2008

Authors and Affiliations

  • Tímea Gombos
    • 1
  • Zsolt Förhécz
    • 1
  • Zoltán Pozsonyi
    • 1
  • Lívia Jánoskuti
    • 1
  • Zoltán Prohászka
    • 1
    • 2
  1. 1.IIIrd Department of Internal Medicine and Szentágothai Knowledge CenterSemmelweis UniversityBudapestHungary
  2. 2.Research Group of Inflammation Biology and ImmunogenomicsHungarian Academy of SciencesBudapestHungary

Personalised recommendations