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Ann Thorac Surg 2008;85:80-87. doi:10.1016/j.athoracsur.2007.06.049
© 2008 The Society of Thoracic Surgeons
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Original Articles: Cardiovascular

Heat Shock Proteins 27, 60, 70, 90{alpha}, and 20S Proteasome in On-Pump Versus Off-Pump Coronary Artery Bypass Graft Patients

Tamas Szerafin, MD, PhDa,*, Konrad Hoetzenecker, MDb,*, Stefan Hacker, MDa, Ambrus Horvath, MDa, Andreas Pollreisz, MDb, Péterffy Árpád, MDa, Andreas Mangold, MDb, Tina Wliszczak, MDb, Martin Dworschak, MDc, Rainald Seitelberger, MDb, Ernst Wolner, MDb, Hendrik J. Ankersmit, MDb,*

a Department of Cardiac Surgery, University of Debrecen, Debrecen, Hungary
b Department of Cardiothoracic Surgery, Medical University of Vienna, Vienna, Austria
c Department of Cardiothoracic Anaesthesia, Medical University of Vienna, Vienna, Austria

Accepted for publication June 15, 2007.

* Address correspondence to Dr Ankersmit, Department of Cardiothoracic Surgery, Medical University of Vienna, Währinger Gürtel 18–20, Vienna, 1090, Austria (Email: hendrik.ankersmit{at}meduniwien.ac.at).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Footnotes
 References
 
Background: The secretion of heat shock protein (HSP) 27, HSP60, HSP70, HSP90{alpha}, 20S proteasome, and their correlations to proinflammatory cytokine interleukin-6 is unknown in patients undergoing on-pump versus off-pump coronary artery bypass graft (CABG) operation.

Methods: Forty patients were included in this explorative study (on- versus off-pump CABG, each n = 20). Serum samples were obtained before and 30 minutes, 60 minutes, and 24 hours after CABG operation. Enzyme-linked immunosorbent assay technique was utilized to determine soluble HSP27, 60, 70, and 90{alpha}, 20S proteasome, and levels of interleukin-6.

Results: Serum levels of HSP are increased in patients undergoing on-pump CABG operation as compared with off-pump CABG technique. These differences were highly significant for HSP27, 70, and 90{alpha} at 60 minutes after initiation of cardiopulmonary bypass (all, p < 0.001). Concentrations of soluble 20S proteasome were increased 24 hours after operation in on- and off-pump CABG patients (p < 0.001) and correlated significantly with the serum content of HSP 27, 70, and 90{alpha} at 60 minutes after initiation of cardiopulmonary bypass (p < 0.001). No correlation was found when comparing interleukin-6 levels with intravascular leakage of HSP and 20S proteasome after CABG operation.

Conclusions: We conclude from our data that the innate immune system is activated owing to spillage of known immune modulatory and apoptosis-associated proteins after CABG operation.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Footnotes
 References
 
Cardiopulmonary bypass (CPB), utilized in on-pump coronary artery bypass graft (CABG) procedure induces a systemic immune response [1, 2]. The release of a variety of mediators has been implicated in the pathogenesis of immune deviation after CABG operation [3, 4]. Previously published data from our group evidenced that patients undergoing CABG operation exhibit within the first 24 hours increased serum levels of soluble endothelial/epithelial apoptosis-specific products (caspase-cleaved cytokeratin 18), a dilution of soluble VCAM and ICAM (due to hypooncotic hemodilution), and a rapid secretion of soluble ST2, a protein derived from the innate immune system with immunosuppressive capacity after coronary revascularization [5–7].

We therefore hypothesized that concentrations of other proteins related to the innate immune system, such as the highly conserved heat shock related proteins and the 20S proteasome, are altered after off- and on-pump CABG procedures. In addition, we explored whether the interleukin-6 (IL-6) content, a protein described in the systemic inflammatory response syndrome [1], correlates with the leakage of HSP and 20S proteasome after CABG operation.

Heat shock proteins belong to a group of proteins termed stress proteins. They are described as highly conserved molecules that fulfil a range of functions including cytoprotection, folding, and translocation of oligomeric proteins. These proteins are present in all cells and can be induced in all species [8]. They are classified into several families named on the basis of their approximate molecular weight (eg, the 27 kDa, HSP27). The HSPs are constitutively expressed in all cells and make up 5% to 10% of the total protein content under normal physiologic conditions. The synthesis of these proteins can be markedly induced (as much as 15% of the total cellular protein content) by a range of cellular insults such as heat, ultraviolet light, or cytotoxic agents that cause protein unfolding, misfolding, and aggregation [8, 9]. In these conditions, HSPs act as molecular chaperones assisting other proteins in achieving proper folding.

A further known chaperon is the 20S proteasome. It is deemed pivotal in the degeneration of epithelium and general wasting syndrome [10]. The proteasome is a multicatalytic protease complex, localized in the cytosol as well as in the nucleus of all eukaryotic cells and is crucially involved in the enzymatic degradation of ubiquitinated proteins. Moreover, it controls numerous physiologic processes, including signal transduction, transcriptional activation, cell-cycle progression, and certain immune cell functions. The proteasome is made up of a cylindrical-shaped core particle, the 20S proteasome, which consists of two sets of seven different {alpha} and β subunits assembled in four heptameric rings. Increased levels of circulating 20S proteasome were recently proposed as markers of cell damage and immunologic activity in various autoimmune diseases, sepsis, and acute liver failure [11–13].

As there is no published comprehensive evaluation of chaperons including HSP27, 60, 70, and 90{alpha}, and 20S proteasome and their relation to IL-6 secretion in respect to on- versus off-pump CABG surgery, we hypothesized that levels of these proteins with known intracellular immune activity are altered in the study cohorts selected. Our results evidence that alteration of HSP 27, 70, and 90{alpha} and 20S proteasome are occurring independently of the induction of IL-6 in patients undergoing on-pump CABG surgery in this nonrandomized, comparative study.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Footnotes
 References
 
Patient Selection, Medication, Technical Aspects
This study protocol was approved by the Ethics Committee of the Medical University of Vienna, Austria (EC-No: 356/2006). Written informed consent was obtained from all patients included in the study. Forty consecutive patients undergoing CABG were evaluated in this study, 20 of whom underwent operation on-pump and 20, off-pump. Exclusion criteria were determined as infections, redo or emergency operations, immunologic disorders or treatment with immunomodulatory drugs (eg, steroids) and acute myocardial infarction less than two weeks before surgery. The two groups did not differ in age, sex, symptoms, or functional class (Table 1).


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  		Table 1 Patient Demographics and Laboratory Data
 
The same anesthesia drugs and muscle relaxants were administered in both groups (midazolam 0.1 to 0.15 mg/kg, fentanyl 0.005 mg/kg; for maintenance, continuous intravenous propofol 0.07 to 0.14 mg · kg–1 · min–1 and inhalation of isoflurane 0.2 to 1.5 vol% plus repetitive fentanyl boli; pipecuronium bromide 0.08 mg/kg or atracuronium 0.5 mg/kg).

On-pump group patients were administered heparin (3 mg/kg sodium heparin [300 IE/kg]). Activated clotting time was determined to be above 600 s. Neutralization was achieved by administration of protamine sulph.

Off-pump patients were administered heparin (1.5 mg/kg sodium heparin [150 IE/kg]). Activated clotting time was held above 300 s during operation. Neutralization with protamine was not necessary in the off-pump CABG group.

For extracorporeal circulation, a standard pump (Pemco, Cleveland, Ohio) and membrane oxygenator (Dideco D-703) were used. Pump flow was set at 2.4 L · min–1 · m–2. Patients were cooled to 32°C, and arrest of the heart’s motion was achieved by anterograde administration of cardioplegia (potassium-magnesium solution).

Off-pump patients were operated on following a routine protocol. Stabilizers (Medtronic, Minneapolis, Minnesota) were used for the exposure of the target vessel.

Serum Samples
Venous blood was drawn preoperatively and 30 minutes, 60 minutes, and 24 hours after initiation of CPB. Serum was obtained after centrifugation. Samples were kept frozen at –20°C until tests were performed.

Heat Shock Proteins 27, 60, and 70
Levels of HSP27, HSP60, and HSP70 were determined using adapted enzyme-linked immunosorbent assay (ELISA) kits for the quantification of intracellular HSP (Duoset IC; R&D Systems, Minneapolis, Minnesota). Ninety-six–well microtiter plates were coated overnight at 4°C with the capture antibody at a concentration of 1 µg/mL. After blocking of plates, serum samples and standard protein in different concentrations were added to the wells. After a washing step, a biotin-labelled antibody was added to each well and incubated for 1 hour. Plates were washed and Streptavidin-HRP was added. Color reaction was achieved using tetramethylbenzidine (TMB; Sigma, St. Louis, Missouri) and was stopped by an acid stop solution. Optical density was measured at 450 nm on an ELISA reader.

Heat Shock Protein 90{alpha}
Serum levels of HSP90{alpha} were measured with a commercially available ready-to-use ELISA kit (Stressgen, Ann Arbor, Michigan). In brief, serum samples and standards were incubated in 96-well microtiter plates, precoated with antihuman HSP90{alpha} antibody. After a washing step, anti-HSP90{alpha}:HRP-conjugated antibody was added, and plates were incubated for 24 hours. Plates were washed and TMB substrate was added. Color development was stopped by an acid stop solution, and optical density was determined at 450 nm. The amount of protein in each sample was calculated according to a standard curve of optical density values constructed for known levels of HSP90{alpha}. The sensitivity of the ELISA has been determined to be 50 pg/mL; the intra-assay variability is stated to be less than 10% by the manufacturer.

20S Proteasome
Microtiter plates were incubated overnight at 4°C with a monoclonal antibody against the {alpha}6-subunit of the 20S proteasome (Biomol, Plymouth Meeting, Pennsylvania). Plates were washed and blocked for 1 hour with 1% BSA in phosphate-buffered saline. Serum samples and different concentrations of a standard protein (Biomol) were added, then plates were sealed and incubated for 24 hours at 4°C. A rabbit polyclonal antibody to 20S proteasome {alpha}/β subunits (Biomol), serving as the detection antibody, was added; and after a washing step, plates were incubated with a peroxidase-labeled donkey anti-rabbit IgG (Jackson ImmunoResearch, Soham, United Kingdom) for another 2 hours. Tetramethylbenzidine served as color substrate. The reaction was stopped by adding 1N sulphuric acid. Plates were read at 450 nm using a Wallac Multilabel counter 1420 (PerkinElmer, Boston, Massachusetts).

Interleukin-6
Serum levels of IL-6 were determined by a commercially available ELISA kit (BenderMedSystems, Vienna, Austria). Assays were performed according to the manufacturer’s instructions. Plates were read at 450 nm on an ELISA reader, and IL-6 contents were calculated comparing optical density values of samples with optical density values of known IL-6 concentrations.

Statistical Analysis
Statistical analysis was performed using SPSS software (SPSS, Chicago, Illinois). Data are given as mean ± standard of the mean. Normal distribution was verified using the Kolmogorov-Smirnov test. Multivariate analysis showed no significant influence of age, body mass index, sex, blood cholesterol, or blood creatinine on the target variables. Unpaired two-sided t tests were performed for independent variables, and paired two-sided t tests for dependent variables. Bonferroni correction was used to calculate p values. All p values less than 0.05 were considered statistically significant. Calculation of significances in correlation tests was performed using the Pearson product-moment correlation coefficient.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Footnotes
 References
 
HSP27 Content Increases Significantly in On- Versus Off-Pump CABG at 60 Minutes
Figure 1A demonstrates that in on-pump CABG versus off-pump CABG patients, a significant rise of soluble HSP27 serum levels occurs at 60 minutes after initiation of CPB (mean levels, 12,058.0 ± 1,103.0 pg/mL versus 4,568.3 ± 465.5 pg/mL; p < 0.001).


Figure 1
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  		Fig 1. (A) Serum heat shock protein (HSP) 27 (pg/mL) before the coronary artery bypass graft (CABG) procedure, at 30 and 60 minutes, and 24 hours after the operation. (B) Serum HSP60 (pg/mL) before the CABG procedure, at 30 and 60 minutes, and 24 hours after the operation. (C) Serum HSP70 before the CABG procedure, at 30 and 60 minutes, and 24 hours after the operation. (D) Serum HSP90{alpha} (pg/mL) before the CABG procedure, at 30 and 60 minutes, and 24 hours after the operation. (E) Serum 20S proteasome (ng/mL) before the CABG procedure, at 30 and 60 minutes, and 24 hours after the operation. (A–E) Diamonds (off pump) and boxes (on pump) represent the mean value; the whiskers, the standard error of the mean (*p < 0.05; **p < 0.01; ***p < 0.001).

 
HSP60 Content Evidences No Alteration in On- Versus Off-Pump CABG at All Timepoints
Figure 1B shows serum levels of soluble HSP60. The mean levels (pg/mL) measured preoperatively, at 30 minutes, 60 minutes, and 24 hours were 1,361.5 ± 217.1, 1,197.8 ± 211.3, 1,314.6 ± 218.7, and 955.5 ± 155.6 in the on-pump group in comparison with 1,548.3 ± 286.5, 1,326.9 ± 273.7, 1,278.2 ± 293.4, and 1,073.5 ± 238.8 in the off-pump group.

HSP70 Content Increases Significantly in On- Versus Off-Pump CABG at 60 Minutes
Serum levels of HSP70 are depicted in Figure 1C. We evidenced a significant increase of HSP70 concentration in the on-pump CABG group at 60 minutes compared with the preoperative values (1,874.7 ± 329.7 pg/mL and 4,558.3 ± 628.9 pg/mL; p < 0.001). After 24 hours, the serum content returned to the preoperative levels. This trend was not observed in the off-pump cohort (not significant). However, the difference between the two study groups reached significance at 30 minutes (on-pump, 2,314.2 ± 418.7 pg/mL; off-pump, 929.2 ± 171.8 pg/mL; p = 0.005) as well as at 60 minutes (on-pump, 4,558.3 ± 628.9 pg/mL; off-pump, 784.9 ± 118.1 pg/mL; p < 0.001).

HSP90{alpha} Content Increases Significantly in On- Versus Off-Pump CABG at 60 Minutes
Figure 1D shows a comparison of serum levels of HSP90{alpha} between the on- and off-pump group. A significant rise of HSP90{alpha} was observed 60 minutes after initiation of the operation (on-pump, 54,855.6 ± 8,400.0 pg/mL; off-pump, 24,402.6 ± 3,504.3 pg/mL; p = 0.003). After 24 hours postoperatively, levels of HSP90{alpha} decreased to preoperative serum levels.

20S Proteasome Increases Significantly in On- Versus Off-Pump Group at 24 Hours
Figure 1E demonstrates the differences of 20S proteasome serum levels in on- versus off-pump patients. Preoperatively, levels in the on-pump CABG group were determined to be 29,888.1 ± 4,387.7 ng/mL; levels in the off-pump CABG group were 23,071.9 ± 2,525.7 ng/mL. A significant difference was reached after 24 hours (on-pump, 50,548.7 ± 8,103.5 ng/mL; off-pump, 19,938.2 ± 2,369.5 ng/mL; p = 0.002). The 20S proteasome levels were heightened in both groups at all time points compared with serum levels of healthy controls (data not shown).

Spillage of 20S Immune Protesome Into Vascular Bed at 24 Hours Correlates With HSP27, 70, and 90{alpha} at 60 Minutes After CABG Operation
Correlation curves of HSP27, 70, and 90{alpha} are shown in Figure 2. The HSP27, 70, and 90{alpha} values at 60 minutes correlated in a positive manner with serum content of the 20S proteasome 24 hours postoperatively (R and p values stated in the graphs).


Figure 2
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  		Fig 2. Correlations between (A) heat shock protein (HSP) 27, (B) HSP70, and (C) HSP90{alpha} (all pg/mL) at 60 minutes as compared with 20S proteasome (ng/mL) serum content after 24 hours.

 
Serum IL-6 Increment After CABG Operation Does Not Correlate With HSP27, 70, 90{alpha} Levels at 60 Minutes and 20S Immune Protesome at 24 Hours
Figure 3 displays calculated correlations between IL-6, HSP chaperones (A, B, C), and 20S protesome (D). No significant correlation was found in the tested variables, indicating that the leakage of HSPs and 20S proteasome and the thoroughly described proinflammatory response after CPB were two independent events (R and p values stated in the graphs).


Figure 3
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  		Fig 3. Correlations between serum content of interleukin-6 (IL-6 [pg/mL]) and chaperons (A) heat shock protein (HSP) 27, (B) HSP70, (C) HSP90, and (D) 20S proteasome.

 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Footnotes
 References
 
In this study, we examined the presence of soluble HSP27, 60, 70, and 90{alpha}, and 20S proteasome in serum samples obtained before and as long as 24 hours postoperatively in on- and off-pump CABG procedures. We confirm previous data showing heightened levels of HSP70 60 minutes after on-pump versus off-pump CABG operation [14]. The HSP27 and 90{alpha} serum concentrations, both proteins known to be related to apoptosis and activation of the immune system, peaked 60 minutes after initiation of the on-pump CABG operation and returned to baseline levels within 24 hours. Moreover, we were able to show a 20S proteasome release into the vascular bed, indicating that systemic cellular degeneration is occurring after on-pump CABG operation. However, no correlation between spilled HSP, 20S proteasome, and secretion of the proinflammatory cytokine IL-6 after CABG operation was found.

Heat Shock Protein 27
We evidenced a twofold increase of HSP27 in the on-pump CABG group compared with off-pump CABG patients. The assumed role of HSP27 in cell hemostasis is a posttranslational modification of newly synthesized proteins. Expression of HSP27 is transiently induced as a response to stress events. Cessation of this stimulus results in an immediate fall of HSP27 concentrations to basic levels. Thus, HSP27 is only upregulated when its cytoprotective properties are required. In this context, known HSP27 functions are (1) maintaining the normal function of cells through interaction with and stabilization of the cytoskeleton and by facilitating the repair or removal of damaged proteins; and (2) preventing apoptosis by interfering with caspase activation sequestering cytochrome c and procaspase 3 as well as modulating redox potentials [15–19]. Owing to measured HSP27 serum levels in our patient collectives, we speculate that apoptosis and alterations in cell cytoskeleton are taking place in patients undergoing CABG operation.

Heat Shock Protein 60
Extracellular liberation of HSP60 was not increased in the investigated patient cohorts. The levels remain stable at time 0, 30 minutes, 60 minutes, and 24 hours postoperatively, and therefore are not discussed.

Heat Shock Protein 70
As previously reported, HSP70 serum levels are increased in the on-pump group compared with off-pump CABG patients [14]. Immune responses are associated with an activation of the nuclear factor kappa B (NF{kappa}B) pathway [20]. Normally found in the cytosol and bound to its inhibitory protein I{kappa}B, NF{kappa}B is activated by a variety of factors including ischemia, oxidative stress, and endotoxin exposure. These factors are known to enable the I{kappa}B kinase (I{kappa}K), which phosphorylates I{kappa}B. The phosphorylated I{kappa}B can be degraded by proteasomes. Liberated NF{kappa}B is able to translocate into the nucleus where it binds to its consensus sequences. Many genes involved in the inflammatory response are rapidly activated in this manner, including inducible nitric oxide synthase, inflammatory cytokines such as tumor necrosis factor-{alpha} and IL-1, inducible cyclooxygenase, as well as chemokines and adhesion molecules. In a fast negative feedback loop, NF{kappa}B also induces I{kappa}B, leading to its own downregulation.

Of specific interest in our context are studies showing that thermal stress leads to inhibition of an inflammatory response. This inhibition was associated with increased levels of HSP70 induction and decreased nuclear NF{kappa}B translocation [21, 22]. It has been speculated that the above described mechanism is responsible for this [23]. This theory was confirmed by Ran and coworkers [24]. From these reports, we conclude that cellular stress is not only related to an upregulation of intracellular HSP70 but also results in increased liberation of HSP70. In the light of recent papers evidencing protective effects of HSP70 application in tumor necrosis factor-{alpha}–induced lethal inflammatory shock [25], liberation of HSP70 by CPB might also downregulate immune reactivity in patients undergoing CABG operation.

Heat Shock Protein 90{alpha}
The major cellular function of HSP90{alpha} involves participation in the organization and maintenance of the cytoarchitecture [26]. The chaperon function of the HSP90 family has been implicated in tumor antigen presentation to T-cells. In a study by Rajagopal and colleagues [27], receptor-mediated endocytosis and antigen presentation was associated with HSP90{alpha} activity [27]. The HSP90{alpha} activity in antigen-presenting cells resulted in an induction of cytotoxic T cells. This chaperon function of HSP90{alpha} may also change the immunogenicity of associated antigen. Therefore, HSP90{alpha} may have immunomodulatory effects through cross-presentation of associated preptides in the context of major histocompatibility complex molecules [28].

20S Proteasome
Despite the rapid elucidation of the proteasome complex in apoptotic signaling cascades, almost no information exists about the biological role of extracellular 20S proteasome. We were able to demonstrate a mean twofold increase of 20S proteasome in the on-pump versus off-pump CABG operation 24 hours after intervention. Such increments have also been evidenced in sepsis and acute liver failure [29]. We assume that the general induction of degeneration of epithelial cells, endothelial cells, and hemolysis of red blood cells after CABG operation leads to spillage of 20S immune proteasome into the vascular bed. We speculate that these increased levels of 20S proteasome are responsible for the induction of a catabolic condition seen in the clinical setting. Others have shown that this catabolic state after major surgery is due to the ubiquitin-proteasome pathway [30, 31]. Of utmost importance was our observation that the secretion of HSP27, 70, and 90{alpha} after 60 minutes correlated significantly with the spillage of 20S proteasome 24 hours after CABG operation. Whether these increased serum 20S proteasome levels are immunogenic as described elsewhere [12] or evidence biological activity will need to be addressed in further studies. However, attempts answering this question have been made by Dahlmann and collegues [32], showing that circulating 20S proteasome obtained from patients suffering from rheumatoid arthritis and lupus erythematosus still have catalytic properties.

In conclusion, HSPs and 20S proteasome, thought to assist in the maintenance of cellular integrity and viability, are leaked into the vascular bed because of stressful stimuli associated with the on-pump CABG procedure. Moreover, they are also involved in antigen presentation, steroid receptor function, intracellular trafficking, nuclear receptor binding, and apoptosis [33, 34]. This is the first time HSPs and 20S proteasome have been described in the extracellular compartment during heart surgery. The novelty of our finding is corroborated by the finding that the augmentation of chaperone content does not correlate with IL-6 cytokine secretion. These data confirm experimental work currently published that evidence the immune modulatory properties of HSP and 20S proteasome. Further in vitro experimental designs are warranted, however, to foster further understanding of immune modulation after CABG operation.


   Footnotes
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Footnotes
References
 
* Tamas Szerafin and Konrad Hoetzenecker contributed equally. Back


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Footnotes
 References
 

  1. Richter JA, Meisner H, Tassani P, et al. Drew-Anderson technique attenuates systemic inflammatory response syndrome and improves respiratory function after coronary artery bypass grafting Ann Thorac Surg 2000;69:77-83.[Abstract/Free Full Text]
  2. Westaby S. Organ dysfunction after cardiopulmonary bypassA systemic inflammatory reaction initiated by the extracorporeal circuit. Intens Care Med 1987;13:89-95.[Medline]
  3. Levy JH, Kelly AB. Inflammation and cardiopulmonary bypass Can J Anaesth 1993;40:1009-1015.[Medline]
  4. McBride WT, Armstrong MA, Crockard AD, McMurray TJ, Rea JM. Cytokine balance and immunosuppressive changes at cardiac surgery: contrasting response between patients and isolated CPB circuits Br J Anaesth 1995;75:724-733.[Abstract/Free Full Text]
  5. Szerafin T, Brunner M, Horvath A, et al. Soluble ST2 protein in cardiac surgery: a possible negative feedback loop to prevent uncontrolled inflammatory reactions Clin Lab 2005;51:657-663.[Medline]
  6. Szerafin T, Horvath A, Moser B, et al. Apoptosis-specific activation markers in on- versus off-pump coronary artery bypass graft (CABG) patients Clin Lab 2006;52:255-261.[Medline]
  7. Oshikawa K, Yanagisawa K, Tominaga S, Sugiyama Y. ST2 protein induced by inflammatory stimuli can modulate acute lung inflammation Biochem Biophys Res Commun 2002;299:18-24.[Medline]
  8. Hightower LE. Heat shock, stress proteins, chaperones, and proteotoxicity Cell 1991;66:191-197.[Medline]
  9. Aufricht C. HSP: helper, suppressor, protector Kidney Int 2004;65:739-740.[Medline]
  10. Tisdale MJ. Pathogenesis of cancer cachexia J Support Oncol 2003;1:159-168.[Medline]
  11. Matthews W, Driscoll J, Tanaka K, Ichihara A, Goldberg AL. Involvement of the proteasome in various degradative processes in mammalian cells Proc Natl Acad Sci USA 1989;86:2597-2601.[Abstract/Free Full Text]
  12. Egerer K, Kuckelkorn U, Rudolph PE, et al. Circulating proteasomes are markers of cell damage and immunologic activity in autoimmune diseases J Rheumatol 2002;29:2045-2052.[Abstract/Free Full Text]
  13. Mitch WE, Goldberg AL. Mechanisms of muscle wastingThe role of the ubiquitin-proteasome pathway. N Engl J Med 1996;335:1897-1905.[Free Full Text]
  14. Dybdahl B, Wahba A, Haaverstad R, et al. On-pump versus off-pump coronary artery bypass grafting: more heat-shock protein 70 is released after on-pump surgery Eur J Cardiothorac Surg 2004;25:985-992.[Abstract/Free Full Text]
  15. Concannon CG, Gorman AM, Samali A. On the role of Hsp27 in regulating apoptosis Apoptosis 2003;8:61-70.[Medline]
  16. Sheth K, De A, Nolan B, et al. Heat shock protein 27 inhibits apoptosis in human neutrophils J Surg Res 2001;99:129-133.[Medline]
  17. Arnaud C, Joyeux M, Garrel C, et al. Free-radical production triggered by hyperthermia contributes to heat stress-induced cardioprotection in isolated rat hearts Br J Pharmacol 2002;135:1776-1782.[Medline]
  18. Latchman DS. Protection of neuronal and cardiac cells by HSP27 Prog Mol Subcell Biol 2002;28:253-265.[Medline]
  19. Vander Heide RS. Increased expression of HSP27 protects canine myocytes from simulated ischemia-reperfusion injury Am J Physiol Heart Circ Physiol 2002;282:H935-H941.[Abstract/Free Full Text]
  20. Barnes PJ, Karin M. Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases N Engl J Med 1997;336:1066-1071.[Free Full Text]
  21. Guzhova IV, Darieva ZA, Melo AR, Margulis BA. Major stress protein Hsp70 interacts with NF-kB regulatory complex in human T-lymphoma cells Cell Stress Chaperones 1997;2:132-139.[Medline]
  22. Heneka MT, Sharp A, Klockgether T, Gavrilyuk V, Feinstein DL. The heat shock response inhibits NF-kappaB activation, nitric oxide synthase type 2 expression, and macrophage/microglial activation in brain J Cereb Blood Flow Metab 2000;20:800-811.[Medline]
  23. Feinstein DL, Galea E, Reis DJ. Suppression of glial nitric oxide synthase induction by heat shock: effects on proteolytic degradation of IkappaB-alpha Nitric Oxide 1997;1:167-176.[Medline]
  24. Ran R, Lu A, Zhang L, et al. HSP70 promotes TNF-mediated apoptosis by binding IKK gamma and impairing NF-kappa B survival signaling Genes Dev 2004;18:1466-1481.[Abstract/Free Full Text]
  25. Van Molle W, Wielockx B, Mahieu T, et al. HSP70 protects against TNF-induced lethal inflammatory shock Immunity 2002;16:685-695.[Medline]
  26. Garnier C, Barbier P, Gilli R, et al. Heat-shock protein 90 (hsp90) binds in vitro to tubulin dimer and inhibits microtubule formation Biochem Biophys Res Commun 1998;250:414-419.[Medline]
  27. Rajagopal D, Bal V, Mayor S, George A, Rath S. A role for the Hsp90 molecular chaperone family in antigen presentation to T lymphocytes via major histocompatibility complex class II molecules Eur J Immunol 2006;36:828-841.[Medline]
  28. Sreedhar AS, Soti C, Csermely P. Inhibition of Hsp90: a new strategy for inhibiting protein kinases Biochim Biophys Acta 2004;1697:233-242.[Medline]
  29. Roth GA, Moser B, Krenn C, et al. Heightened levels of circulating 20S proteasome in critically ill patients Eur J Clin Invest 2005;35:399-403.[Medline]
  30. Minnaard R, Wagenmakers AJ, Combaret L, et al. Ubiquitin-proteasome-dependent proteolytic activity remains elevated after zymosan-induced sepsis in rats while muscle mass recovers Int J Biochem Cell Biol 2005;37:2217-2225.[Medline]
  31. Beehler BC, Sleph PG, Benmassaoud L, Grover GJ. Reduction of skeletal muscle atrophy by a proteasome inhibitor in a rat model of denervation Exp Biol Med (Maywood) 2006;231:335-341.[Abstract/Free Full Text]
  32. Zoeger A, Blau M, Egerer K, Feist E, Dahlmann B. Circulating proteasomes are functional and have a subtype pattern distinct from 20S proteasomes in major blood cells Clin Chem 2006;52:2079-2086.[Abstract/Free Full Text]
  33. Kiang JG, Tsokos GC. Heat shock protein 70 kDa: molecular biology, biochemistry, and physiology Pharmacol Ther 1998;80:183-201.[Medline]
  34. Giffard RG, Yenari MA. Many mechanisms for hsp70 protection from cerebral ischemia J Neurosurg Anesthesiol 2004;16:53-61.[Medline]

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N. Zou, L. Ao, J. C. Cleveland Jr., X. Yang, X. Su, G.-Y. Cai, A. Banerjee, D. A. Fullerton, and X. Meng
Critical role of extracellular heat shock cognate protein 70 in the myocardial inflammatory response and cardiac dysfunction after global ischemia-reperfusion
Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2805 - H2813.
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J. Feng and F. W. Sellke
Invited commentary
Ann. Thorac. Surg., January 1, 2008; 85(1): 87 - 88.
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