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European Journal of Heart Failure 2006 8(8):810-815; doi:10.1016/j.ejheart.2006.03.004
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© 2006 European Society of Cardiology

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

Mamoru Satoh*, Yudai Shimoda, Tomonari Akatsu, Yuh Ishikawa, Yoshitaka Minami and Motoyuki Nakamura

Second Department of Internal Medicine, Iwate Medical University School of Medicine Uchimaru 19-1, Morioka 020-8505, Iwate, Japan

* Corresponding author. Tel.: +81 19 651 5111; fax: +81 19 651 0401. E-mail address: m_satoh{at}imu.ncvc.go.jp


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 
Background: Recent studies have shown that heat shock protein (HSP) 70 may serve as a "damage signal" to the immune system and could be the endogenous ligand for Toll-like receptor (TLR) 4 mediating synthesis of inflammatory cytokines.

Aims: To explore the relationship between circulating HSP70 levels and activation of monocyte TLR4 and myocardial damage after AMI.

Methods and results: This study examined circulating HSP70 and monocyte TLR4 levels in 52 patients with AMI and 20 controls, and analyzed ex vivo inflammatory cytokine productions using HSP70-stimulated monocytes. Circulating HSP70 levels were higher in AMI patients on day 1 after onset than in controls and remained elevated in AMI patients 14 days after onset. HSP70 levels were positively correlated with monocyte TLR4, plasma interleukin-6 and tumor necrosis factor-{alpha} levels in AMI patients. HSP70 levels 14 days after onset were higher in AMI patients with heart failure (n=15) than in those without heart failure. In our in vitro study, HSP70-stimulated monocytes resulted in dose-dependent TLR4 expression and release of inflammatory cytokines. TLR4 antibody inhibited inflammatory cytokines release.

Conclusions: Elevated circulating levels of HSP70 may be involved in TLR4 signal-mediated immune response and the progression of heart failure after AMI.

Key Words: Flow cytometry • Heart failure • Interleukin 6 • Real-time PCR • Tumor necrosis factor-{alpha}

Received December 1, 2005; Revised January 23, 2006; Accepted March 9, 2006


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 
Several studies have demonstrated that peripheral monocytosis is associated with systemic inflammatory reaction after acute myocardial infarction (AMI) [1,2]. Monocyte-related inflammatory cytokines, such as interleukin (IL) 6 and tumor necrosis factor (TNF)-P, may contribute to the inflammatory and subsequent immune responses after AMI [3,4]. Toll-like receptor (TLR) 4 specifically signals cellular responses to bacterial lipopolysaccharide (LPS) in conjunction with accessory molecules on monocytes [5,6]. Our previous study and Methe's report have demonstrated that activation of monocyte TLR4 signal was related to its downstream release of inflammatory cytokines in patients with AMI [7,8]. Nevertheless, noninfectious endogenous danger signals may be released after ischaemic change, thus activating a systemic inflammatory reaction.

Heat shock proteins (HSPs) are the most phylogenetically conserved proteins present in all prokaryotes and eukaryotes [9,10]. Among HSPs, HSP70 is a potent endogenous activator of the innate immune system as a putative TLR ligand and is capable of stimulating inflammatory cytokine production by the monocyte-macrophage system [11,12]. Dybdahl et al. have recently shown that circulating HSP70 is related to the extent of myocardial damage and may have a role in the systemic inflammatory response against ischaemic myocardial injury [13]. However, the relationship between circulating HSP70 and monocyte TLR4 signalling in AMI patients has not been explored. Therefore, our aim was to determine whether circulating HSP70 is related to the TLR4 signal in circulating monocytes obtained from patients with AMI and whether this is related to myocardial damage after AMI.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 Acknowledgments
 References
 
2.1. Study population
Peripheral blood samples were obtained from 52 patients with first Q-wave AMI. All patients were admitted within 24 h of the onset of AMI. Anterior AMI was diagnosed in 39 patients and inferior AMI in 13 patients. Further blood samples were taken from AMI patients 24 h and 14 days after the onset of AMI. Patients were excluded from the study if they had clinical signs of acute infection, severe renal failure or rheumatoid disease, or if they were suspected of having a malignant or primary wasting disorder. All patients were enrolled regardless of whether they were undergoing primary percutaneous coronary intervention (n=48) and thrombolysis (n=5). Echocardiography (Acuson Sequoia Echo 256, Siemens) was used to determine left ventricular ejection fraction (LVEF) 14 days after the onset of AMI. The presence of heart failure (HF) was determined during admission, within 14 days of the onset of AMI, and was defined as class 2 or greater according to Killip's classification or subset II or greater according to Forrester's classification.

Blood samples were also obtained from 20 healthy subjects with normal ECG and echocardiographic findings, who acted as controls. Healthy subjects had not had any illnesses such as cardiac disease or infectious illness and were taking no medications. The study protocol was approved by our hospital ethics committee and informed consent was obtained from all subjects.

2.2. Blood sampling
Peripheral blood (20 mL) was obtained from both AMI patients and controls for isolation of monocytes and plasma. Peripheral blood mononuclear cells (PBMC) were isolated by density gradient centrifugation over Ficoll-Paque (Sigma). Monocytes were isolated from PBMC by adherence to a plastic dish (120 min, 37 °C). Monocytes were detached from the plastic dish by incubation in cold phosphate-buffered saline. They were then resuspended at a final concentration of 1x106 cells/mL in RPMI1640 (Sigma).

2.3. Plasma analysis
Plasma samples were obtained from AMI patients and healthy subjects. Circulating HSP70 was measured with a StressXpressTM HSP70 enzyme linked immunosorbent assay kit (EKS-700, Stressgen Bioreagents, Victoria, British Columbia, Canada; sensitivity 500 pg/mL, internal and intra-assay coefficients of variation <10%). Plasma concentrations of IL-6 and TNF-P were measured using a Bio-Plex system which combined the principle of a sandwich immunoassay with Luminex fluorescent-bead-based technology (Bio-Rad Laboratory, sensitivity 0.25 pg/mL) [14]. Cardiac troponin T (cTnT) was measured by chemiluminescent enzyme immunoassay with detection ranges of 0.01-25 ng/mL. High sensitivity C-reactive protein (hsCRP) was quantified by a latex-enhanced immunonephelometric assay (detection range: 3.5-220 mg/L).

2.4. Extraction of total RNA
Total RNA was extracted from monocytes by the acid guanidinium thiocyanate-phenol-chloroform method and treated with DNase I (Gibco BRL) [15].

2.5. Quantitative real-time RT-PCR
The published sequence for human TLR4 was used for construction of primers and TaqMan probe (forward primer: 5' TGA TTG TTG TGG TGT CCC A 3', reverse primer: 5' TGT CCT CCC ACT CCA GGT AA 3' and TaqMan probe: 5' TCC TGC AGA AGG TGG AGA AGA CCC T 3') [16]. To normalize TLR4 mRNA expression for sample-to-sample differences in RNA input, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was amplified as an internal control (PE Biosystem, Foster City, CA, USA). TLR4 mRNA expression levels were analyzed using a quantitative real-time RT-PCR method as previously described [8].

2.6. Flow cytometric analysis
The amount of TLR4 and CD14 on the monocyte cell surface was measured by fluorescence-activated cell sorting (FACS). Isolated monocytes were incubated with PerCP-conjugated CD14 antibody (Becton Dickinson) and FITC-conjugated mouse anti-human TLR4 antibody (Santa Cruz). Isotype-matched irrelevant control IgG was used as a control (Becton Dickinson).

Five thousand CD14-positive events were measured on a FACScan flow cytometer and analyzed with CellQuest software (Becton Dickinson). CD14-positive cells were selected on the basis of PerCP emission and side scatter granularity. Histograms were then generated using CD14-positive cells, which allowed measurement of intracellular TLR4 levels, and isotype controls using mean fluorescence intensity (MFI).

2.7. In vitro studies
Isolated monocytes from 10 AMI patients (1 day after onset) and 10 healthy subjects were resuspended in activating medium (RPMI 1640 with recombinant human (rhu) HSP70 protein [NSP-555, Stressgen Bioreagents], 10% heat-inactivated FCS [GIBCO BRL], penicillin and streptomycin). To explore the role of TLR4 in HSP70-induced activation of monocytes, isolated cells were preincubated in RPMI 1640 medium for 30 min with 10 µg/mL of anti-TLR4 (clone HTA125, Kamiya Biomedical Company) before addition of rhu HSP70 protein (4.0 µg/mL). They were then incubated in sterile polypropylene tubes (Becton Dickinson), in order to prevent adherence of cells, for 6 h at 37 °C in 5% CO2. Cell viability was >85% in all experiments as assessed by trypan blue exclusion of monocytes (Gibco BRL). Endotoxin concentrations were tested in all media and buffers used in this study and were <10 pg/mL (Limulus amoebocyte lysate test).

2.8. Statistical analysis
All values are presented as mean±S.E. Kolmogorov-Smirnov analysis was performed to assess data distribution. Unpaired t-test was performed for normally distributed data and nonparametric Mann-Whitney test was performed when this was not appropriate. In AMI patients, changes in measurements were determined by comparing the mean values for days 1 and 14 using one-way analysis of variance test with Dunnett post hoc test. Spearman correlation coefficients were used to examine the relationship between HSP70 and TLR4 levels and clinical parameters. A value of P<0.05 was considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 Acknowledgments
 References
 
3.1. Baseline characteristics
Baseline characteristics of AMI patients and healthy subjects are shown in Table 1. Although peak WBC count was higher in AMI patients than in healthy subjects, there was no significant difference in the other baseline data between the two groups.


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  		Table 1 Baseline characteristics of the study populations

 
3.2. Circulating levels of HSP70
Circulating levels of HSP70 were significantly higher in AMI patients 1 day after onset than in healthy subjects (1254.4±102.3 pg/mL vs. 545.3±11.5 pg/mL, P<0.01). Although HSP70 levels decreased in AMI patients 14 days after onset, they remained higher than levels in healthy subjects (625.8±15.3 pg/mL, P<0.05).

3.3. TLR4 signal and myocardial damage
Circulating HSP70 levels were positively correlated with monocyte TLR4 levels in patients with AMI (Fig. 1). There was a weak positive correlation between HSP70 levels and plasma concentrations of IL-6 and TNF-P in AMI patients 1 day after onset (HSP70 vs. IL-6: r=0.42, P<0.01; HSP70 vs. TNF-P: r=0.37, P<0.01). TLR4 levels (both mRNA and MFI) and plasma IL-6 and TNF-P concentrations were elevated in AMI patients (1 and 14 days after onset) compared with healthy subjects (Table 2). There was no significant correlation between HSP70 levels and plasma IL-6 and TNF-P concentrations in healthy subjects.


Figure 1
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  		Fig. 1 Correlation between circulating HSP70 and monocyte TLR4 levels 1 day after AMI. (A) HSP70 vs. TLR4 MFI, r=0.65, P<0.01. (B) HSP70 vs. TLR4 mRNA, r=0.66, P<0.01.

 


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  		Table 2 TLR4 levels and plasma IL-6 and TNF-P concentrations in AMI patients and healthy subjects

 
Circulating HSP70 levels were positively correlated with cTnT levels at 1 day after AMI and peak CK levels (HSP70 vs. cTnT: r=0.33, P = 0.01; HSP70 vs. peak CK: r=0.30, P=0.04). There was no significant relationship between HSP70 and hsCRP levels in AMI patients.

3.4. Relationship between clinical data and HSP70 levels
HF was observed in 15 of 52 AMI patients during the 14 days following onset of AMI. Circulating levels of HSP70 were significantly higher in AMI patients with HF than in those without HF (Fig. 2). Fourteen days after onset, circulating levels of HSP70 were negatively correlated with LVEF (Fig. 3).


Figure 2
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  		Fig. 2 Comparison of circulating HSP70 levels between AMI patients with HF and those without HF. HF=AMI patients with HF, non-HF=AMI patients without HF. *P<0.01 versus HSP70 levels in AMI patients without HF.

 


Figure 3
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  		Fig. 3 Correlation between circulating HSP70 levels and LVEF 14 days after AMI. HSP70 levels vs. LVEF, r=–0.44, P=0.01.

 
3.5. In vitro study
To explore the role of TLR4 in HSP70 activation of cells, we used cultured peripheral monocytes obtained from AMI patients 1 day after onset. The rhu HSP70-stimulated monocytes resulted in dose-dependent TLR4 expression and release of IL-6 and TNF-P (Fig. 4). Monoclonal antibody against TLR4 inhibited the HSP70-induced IL-6 and TNF-P responses (Fig. 4C and D).


Figure 4
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  		Fig. 4 Cultured monocytes stimulated with rhu HSP70. (A and B) HSP70-stimulated monocyte TLR4 levels (A: TLR4 MFI, B: TLR4 mRNA). (C) Supernatant IL-6 levels stimulated with rhu HSP70 (1.0 to 4.0 µg/mL). (D) Supernatant TNF-P levels stimulated with rhu HSP70 (1.0 to 4.0 µg/mL). Anti-TLR4=IL6 or TNF-P levels stimulated with HSP70 (4 µg/mL) after preincubation with monoclonal antibody against TLR4 (10 µg/mL). *P<0.01 versus IL-6 or TNF-P level stimulated with HSP70.

 
TLR4 levels did not respond to rhu HSP70 (1.0 to 3.0 µg/mL) in monocytes obtained from healthy subjects. TLR4 levels were slightly increased in high dose HSP70 (4.0 µg/mL)-stimulated monocytes obtained from healthy subjects (TLR4 mRNA=8.97±0.45, TLR4 MFI=7.13±0.76), but these levels were significantly lower in healthy subjects than in AMI patients (all P<0.01).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
Acknowledgments
 References
 
The main finding in the present study is the close relationship between increased HSP70 circulation and the activation of monocyte TLR4 signal in AMI patients. Furthermore, circulating levels of HSP70 are correlated with inflammatory cytokines and are a marker of myocardial damage. In addition, our in-vitro study suggests that HSP70 release is involved in inflammatory cytokine production through the monocyte TLR4 signal.

4.1. Circulating HSP70 levels in AMI patients
We have shown an increase in circulating levels of HSP70 in AMI patients compared with healthy subjects and this was seen to persist 14 days after AMI. An experimental study has demonstrated that myocardial HSP70 production may be induced in the failing heart after ischaemic myocardial injury [17]. In hypoxic rabbit heart, HSP70 protein is abundantly present in coronary vessels and cardiomyocytes, suggesting that circulating HSP70 may be released from the ischaemic heart itself [18]. However, a functional mechanism for HSP70 in the ischaemic heart remains uncertain. Asea et al. reported that HSP70 functions not only as a molecular chaperone, but also as an activator of the immune system capable of inflammatory cytokine production [11]. A murine macrophage cell line model has demonstrated that HSP70 activates the TLR4 signalling pathway and classifies HSP70 as an endogenous natural adjuvant [19]. Moreover, HSP70 dose-dependently induces the downstream production of inflammatory cytokines [19]. The present study showed that circulating HSP70 levels were positively correlated with monocyte TLR4 levels (both mRNA and protein levels) in patients with AMI. There was a positive correlation between HSP70 levels and plasma inflammatory cytokine (IL6 and TNF-P) levels. Furthermore, our in vitro study has shown that recombinant HSP70 indeed induced IL-6 and TNF-P release from monocytes in a dose-dependent manner. As a putative monocyte TLR4 ligand, the release of HSP70 in response to myocardial ischaemic damage has been suggested to activate a systemic immune response [20]. These observations suggest that activation of monocyte TLR4 signalling via the release of HSP70 from the ischaemic heart may be involved in systemic inflammatory reaction.

4.2. Clinical implications
Another important finding of this study is that circulating HSP70 levels were positively correlated with cTnT and CK levels. Both cTnT and CK levels are a reflection of infarct size after AMI [21]. In agreement with our findings, Dybdahl et al. have reported that circulating HSP70 levels were positively correlated with cTnT levels and negatively correlated with LVEF the first day after AMI [13]. The present study demonstrated that an increase in circulating HSP70 levels was significantly related to LV dysfunction and the presence of HF 14 days after AMI. Our previous study demonstrated that the activation of TLR4 signalling and downstream inflammatory cytokine release in circulating monocytes may be involved in the development of HF after AMI [8]. Activation of peripheral monocytes is involved in adverse outcomes and adverse LV remodelling after AMI [1,2]. Our vitro study suggests a direct link between monocyte TLR4 signal and HSP70 as major TLR4 ligand. Although putative ligands for TLR4 have not been examined, a recent study demonstrates that, in TLR4-deficient mice, there is reduced tissue inflammation and myocardial infarction after ischaemia/reperfusion injury as compared with wild-type animals [22]. These observations suggest that circulating HSP70 may be induced by ischaemic myocardial damage and may activate monocyte TLR4 signal and downstream release of inflammatory cytokines. HSP70 and TLR4 levels 14 days after AMI were positively correlated with plasma IL-6 and TNF-P levels. Transgenic mouse models overexpressing IL-6 or TNF-P have demonstrated that both IL-6 and TNF-P contribute to clinical and physiological aspects of HF including progression of LV dysfunction, LV remodelling and myocyte apoptosis [23,24]. Although activated monocyte TLR4 signal may not directly reflect myocardial activation of TLR4 signal, the secretion of IL-6 and TNF-P through downstream TLR4 signal may induce the progression of LV dysfunction after AMI. The present study suggests the intriguing possibility that HSP70 may have therapeutic potential for preventing the progression of LV dysfunction after AMI.

4.3. Conclusions
The present study demonstrates a close link between circulating HSP70 and monocyte TLR4 signal in AMI patients. Increased HSP70 levels may be involved in TLR4-mediated immune response and the progression of heart failure after AMI.


   Acknowledgments
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgments
References
 
This study was supported by the Open Translational Research Center, Advanced Medical Science Center, Iwate Medical University.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 

  1. Maekawa Y., Anzai T., Yoshikawa T., et al. Prognostic significance of peripheral monocytosis after reperfused acute myocardial infarction: a possible role for left ventricular remodeling. J Am Coll Cardiol (2002) 39:241–246.[Abstract/Free Full Text]
  2. Furman M.I., Gore J.M., Anderson F.A., et al. Elevated leukocyte count and adverse hospital events in patients with acute coronary syndromes: findings from the Global Registry of Acute Coronary Events (GRACE). Am Heart J (2004) 147:42–48.[CrossRef][Web of Science][Medline]
  3. Tashiro H., Shimokawa H., Yamamoto K., et al. Monocyte-related cytokines in acute myocardial infarction. Am Heart J (1995) 130:446–452.[CrossRef][Web of Science][Medline]
  4. Marx N., Neumann F.J., Ott I., et al. Induction of cytokine expression in leukocytes in acute myocardial infarction. J Am Coll Cardiol (1997) 30:165–170.[Abstract]
  5. Lien E., Means T.K., Heine H., et al. Toll-like receptor 4 imparts ligand-specific recognition of bacterial lipopolysaccharide. J Clin Invest (2000) 105:497–504.[Web of Science][Medline]
  6. Hoshino K., Takeuchi O., Kawai T., et al. Cutting edge: toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J Immunol (1999) 162:3749–3752.[Abstract/Free Full Text]
  7. Methe H., Kim J.O., Kofler S., Weis M., Nabauer M., Koglin J. Expansion of circulating toll-like receptor 4-positive monocytes in patients with acute coronary syndrome. Circulation (2005) 111:2654–2661.[Abstract/Free Full Text]
  8. Satoh M., Shimoda Y., Maesawa C., et al. Activated toll-like receptor 4 in monocytes is associated with heart failure after acute myocardial infarction. Int J Cardiol (2005) [Electronic publication ahead of print].
  9. Lindquist S., Craig E.A. The heat shock proteins. Annu Rev Genet (1988) 22:631–677.[CrossRef][Web of Science][Medline]
  10. Hartl F.U., Hayer-Hartl M. Molecular chaperones in the cytosol: form nascent chain to folded protein. Science (2002) 295:1852–1858.[Abstract/Free Full Text]
  11. Asea A., Kraeft S.K., Kurt-Jones E.A., et al. HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat Med (2000) 6:435–442.[CrossRef][Web of Science][Medline]
  12. Vabulas R.M., Ahmad-Nejad P., Ghose S., Kirschning C.J., Issels R.D., Wagner H. HSP70 as endogenous stimulus of the Toll/interleukin-1 receptor signal pathway. J Biol Chem (2002) 277:15107–15112.[Abstract/Free Full Text]
  13. Dybdahl B., Slørdahl S.A., Waage A., Kierulf P., Espevik T., Sundan A. Myocardial ischemia and the inflammatory response: release of heat shock protein 70 after myocardial infarction. Heart (2005) 91:299–304.[Abstract/Free Full Text]
  14. de Jager W., te Velthuis H., Prakken B.J., Kuis W., Rijkers G.T. Simultaneous detection of 15 human cytokines in a single sample of stimulated peripheral blood mononuclear cells. Clin Diagn Lab Immunol (2003) 10:133–139.[CrossRef][Medline]
  15. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem (1987) 162:156–159.[Web of Science][Medline]
  16. Medzhitov R., Preston-Hurlburt P., Janeway C.A. Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature (1997) 388:394–397.[CrossRef][Web of Science][Medline]
  17. Tanonaka K., Yoshida H., Toga W., Furuhama K., Takeo S. Myocardial heat shock proteins during the development of heart failure. Biochem Biophys Res Commun (2001) 283:520–525.[CrossRef][Web of Science][Medline]
  18. Rafiee P., Shi Y., Pritchard K.A. Jr., et al. Cellular redistribution of inducible Hsp70 protein in the human and rabbit heart in response to the stress of chronic hypoxia: role of protein kinases. J Biol Chem (2003) 278:43636–43644.[Abstract/Free Full Text]
  19. Vabulas R.M., Ahmad-Nejad P., Ghose S., Kirschning C.J., Issels R.D., Wagner H. HSP70 as endogenous stimulus of the Toll/interleukin-1 receptor signal pathway. J Biol Chem (2002) 277:15107–15112.[Abstract/Free Full Text]
  20. Dybdahl B., Wahba A., Lien E., et al. Inflammatory response after open heart surgery: release of heat-shock protein 70 and signaling through toll-like receptor-4. Circulation (2002) 105:685–690.[Abstract/Free Full Text]
  21. Collinson P.O., Stubbs P.J., Kessler A.C. Multicentre Evaluation of Routine Immunoassay of Troponin T Study. Multicentre evaluation of the diagnostic value of cardiac troponin T, CK-MB mass, and myoglobin for assessing patients with suspected acute coronary syndromes in routine clinical practice. Heart (2003) 89:280–286.[Abstract/Free Full Text]
  22. Oyama J., Blais C. Jr., Liu X., et al. Reduced myocardial ischemia-reperfusion injury in toll-like receptor 4-deficient mice. Circulation (2004) 109:784–789.[Abstract/Free Full Text]
  23. Bryant D., Becker L., Richardson J., et al. Cardiac failure in transgenic mice with myocardial expression of tumor necrosis factor-P. Circulation (1998) 97:1375–1381.[Abstract/Free Full Text]
  24. Hirota H., Yoshida K., Kishimoto T., Taga T. Continuous activation of gp130, a signal-transducing receptor component for interleukin 6-related cytokines, causes myocardial hypertrophy in mice. Proc Natl Acad Sci U S A (1995) 92:4862–4866.[Abstract/Free Full Text]

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