(Circulation. 2000;102:14.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Serum Soluble Heat Shock Protein 60 Is Elevated in Subjects With Atherosclerosis in a General Population
From the Institute for Biomedical Aging Research, Austrian Academy of Sciences, Innsbruck (Q.X., M.M., G.W.); the Department of Internal Medicine, University Hospital of Vienna (G.S.), Vienna, Austria; the Department of Neurology (J.W., S.K.), Institute for General and Experimental Pathology (H.P., G.W.), University of Innsbruck, Medical School, Innsbruck, Austria; and the Department of Internal Medicine, Hospital of Bruneck, Italy (G.E., F.O.).
Correspondence to Dr Qingbo Xu, Institute for Biomedical Aging Research, Austrian Academy of Sciences, Rennweg 10, A-6020 Innsbruck, Austria. E-mail qingbo.xu{at}oeaw.ac.at
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Abstract |
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Background—Work from our laboratory has proven that increased titers of anti-heat shock protein 60 (HSP60) antibodies are associated with atherosclerosis and that HSP60-reactive T-cells are present in atherosclerotic lesions. Recent studies from others demonstrated that HSP60 directly activates endothelial cells and macrophages.
Methods and Results—To explore the possibility that HSP60
exists in the circulation, where it could exert its functions, we
performed a population-based study with 826 subjects aged 40 to 79
years. The following items were measured in all participants: serum
soluble HSP60 (sHSP60); anti-Escherichia coli
lipopolysaccharide; anti-HSP65,
anti-Chlamydia, and anti-Helicobacter
pylori antibodies; and a variety of acute phase reactants
(C-reactive protein, 
1-antitrypsin, and ceruloplasmin)
and markers of systemic inflammation. Carotid
atherosclerosis was assessed twice (1990 and 1995), and
15 other risk factors were evaluated. Our data show that levels of
sHSP60 were significantly elevated in subjects with prevalent/incident
carotid atherosclerosis and that these levels were
correlated with common carotid artery intima/media thickness. Multiple
logistic regression analysis documented these associations as
independent of age, sex, and other risk factors. Interestingly, sHSP60
was also correlated with anti-lipopolysaccharide,
anti-Chlamydia and anti-HSP60 antibodies, various
markers of inflammation, and the presence of chronic infections. The
risk of atherosclerosis associated with high sHSP60
levels was amplified when subjects had clinical and/or laboratory
evidence of chronic infections.
Conclusions—Our data provide the first evidence of a strong correlation between sHSP60 and atherosclerosis, suggesting that sHSP60 may play important roles in activating vascular cells and the immune system during the development of atherosclerosis.
Key Words: heat shock proteins • chaperonin 60 • aging • infection • inflammation • atherosclerosis
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Introduction |
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In response to stress stimuli, including high temperature, mechanical stress, infections, surgical stress, and oxidant and cytokine stimulation, cells produce high levels of heat shock protein (HSP) to protect themselves against these unfavorable conditions.1 2 HSPs belong to a group of
2
dozen proteins and cognates that show highly homologous sequences
between different species, from bacteria to humans. They are highly
expressed in cardiovascular tissues.2 3 4
Recently, reports from 2 independent groups have demonstrated that both
chlamydial and human HSP60 have a cytokine-like activity and
induce tumor necrosis factor- and matrix metalloproteinase
production in human and mouse
macrophages.5 6 Interestingly, both chlamydial and
human HSP60 induced E-selectin, intercellular adhesion molecule–1
(ICAM-1), and vascular cell adhesion molecule-1 expression and
interleukin-6 production in endothelial
cells.7 These findings suggest that HSP60 directly
stimulates vascular endothelial cells, leading to an
inflammatory response, which contributes to the pathophysiology of
atherosclerosis.
Data from our laboratory have shown that atherosclerotic lesions can be induced in normocholesterolemic rabbits by immunization with recombinant mycobacterial HSP65.8 Levels of serum antibodies to HSP65 were significantly increased in clinically healthy human subjects with carotid atherosclerosis compared with those without lesions. The elevation of antibody levels was independent of age, sex, and other classic risk factors.9 Because HSPs show a high degree of amino acid homology between different species from prokaryotes to humans,1 2 3 4 an autoimmune reaction may be evoked because of the immunological cross-reaction between microbial and human HSP60.10
The question arose regarding whether HSP60, which is normally an intracellular protein, exists in the circulation of healthy individuals, where it could directly contact the arterial wall and immune cells. The present study was designed to assess the serum levels of soluble HSP60 (sHSP60) in the general community (Bruneck study) and to investigate its association with the development of carotid atherosclerosis. We had a special focus on potential interactions with chronic infections or inflammation.
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Methods |
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Subjects
Population recruitment was performed as part of the Bruneck Study.11 12 13 14 The survey area is located in the north of Italy (Bolzano province). Special features of the study design and protocol have been described in detail previously.11 12 13 14 In brief, in 1990, the study population was recruited as a sex- and age-stratified random sample of all inhabitants of Bruneck aged 40 to 79 years, such that 125 women and 125 men in each decade, from the 5th to 8th decades of age, were selected (n=1000). A total of 93.6% of these subjects finally participated in the study. Among these subjects, 58 died between the summer of 1990 and 1995. At the first re-evaluation of the study cohort in 1995, the follow-up rate among survivors was high (96.5%; n=826).15 These 826 subjects were the basis for the current study. All participants gave their informed consent before entering the study.
sHSP60 Assays
sHSP60 was determined as part of the 1995
evaluation.11 Blood was obtained after subjects had fasted
and abstained from smoking overnight.11 A sandwich
enzyme-linked immunosorbent assay (ELISA) was performed using 2 types
of monoclonal antibodies against different epitopes of HSP60
(II-1316 and ML-3017 ). In short, 96-well
microtiter plates were coated with 1 µg/mL PBS of the antibody II-13
overnight, washed with PBS, and incubated with 100 µL of human serum
diluted in PBS (1:10). After washing, biotin-labeled IgG ML-30 (1
µg/mL) was added to the plates and incubated at room temperature for
1 hour. Streptavidin conjugated with horseradish peroxidase was
added and developed with the substrate. Absorbance at 410 nm was
measured after 30 minutes. A serum concentration (in ng/mL) of sHSP60
was calculated according to the standard curves obtained by using
recombinant human HSP60 (StressGen Biotechnology Co) in the
sandwich ELISA.
Chromatography and Western Blot Analysis
Monoclonal antibody II-13 was coupled to supports using the
Affi-Gel HZ Immunoaffinity kit (Bio-Rad) according to the
manufacturer’s instructions. sHSP60 was separately isolated from sera
with higher sHSP60 levels from several subjects. Isolated proteins were
electrophoresed, transferred to the membrane, probed with the antibody,
and visualized with an enhanced chemiluminescent kit (Amersham
Co).18
Assays of Anti-Lipopolysaccharide, Anti-HSP65,
Anti-Chlamydia, and Anti-Helicobacter
pylori Antibodies
The procedure used for determining
anti-lipopolysaccharide (LPS) antibodies was similar to that
described elsewhere.19 In short, microtiter plates were
coated with 1 µg/mL polylysine in PBS (Sigma) at 37°C for 1 hour;
they were then washed and incubated with Escherichia coli
LPS (Sigma) overnight. After washing, the plates were incubated with
100 µL of human serum diluted in PBS (1:10 to 1:5120). A serum
dilution was considered positive for antibodies against LPS if the
optical density absorbance at 410 exceeded 0.200. Serum anti-HSP65
antibodies were measured using the ELISA, as described
previously.9 Anti-Chlamydia and
anti-H. pylori antibodies were determined using commercial
kits (Medac) according to the manufacturer’s
instructions.18
Determination of Carotid Atherosclerosis
The ultrasound protocol involves scanning the internal (bulbous
and distal segments) and common carotid arteries (proximal and distal
segments) on both sides with a 10-MHz imaging probe and a 5-MHz
Doppler.11 12 13 14 Atherosclerotic lesions were defined by
the following 2 ultrasound criteria: (1) wall surface (protrusions into
the lumen or roughness of the arterial boundary) and (2)
wall texture (echogenicity). A sensitive and reproducible
atherosclerosis score was calculated by the addition of
all plaque diameters. The accuracy of this procedure was established
previously.11 Incident atherosclerosis was
defined as the occurrence of new plaques in previously normal segments
(1990 to 1995). Intima/media thickness was also documented, and it was
correlated with both the atherosclerosis scores
(r=0.64) and the 5-year changes in the scores
(r=0.48).
Clinical History and Examination
The average number of cigarettes smoked per day and the
pack-years smoked (used as a measure of cumulative exposure) were noted
for each smoker and ex-smoker. Regular alcohol consumption was assessed
in terms of grams/day. Systolic and diastolic blood
pressures were taken with a standard mercury sphygmomanometer after
10 minutes of rest while the subject was in a sitting position. The
values used in the current analysis were means of 3
measurements taken by the same investigator at 1-hour intervals.
Hypertension was defined by a blood pressure 160/95 or the current
use of antihypertensive drugs. A standardized oral glucose tolerance
test (75 g of glucose in 10% solution) was performed in all subjects
except those with well-established diabetes mellitus. Diabetes mellitus
was diagnosed when fasting glucose levels exceeded 7.8 mmol/L (140
mg/dL) and/or a 2-hour value was >11.1 mmol/L (200 mg/dL) (World
Health Organization criteria). The body mass index and waist-to-hip
ratio were used as obesity indices. Subjects with chronic infections
(n=268) were identified by extensive clinical and laboratory screening,
as described elsewhere.20
Other Laboratory Assays
Total and HDL cholesterol were determined
enzymatically (CHOD-PAP and GOD-PAP method, Merck; coefficient
variation [CV], 2.2% to 2.4%), lipoprotein(a) concentrations were
determined with ELISA (Immuno; CV, 3.5% to 6.3%), and apolipoproteins
were determined with a nephelometric fixed-time method (apolipoprotein
AI: CV, 5.7%; apolipoprotein B: CV, 2.4%).21 22 LDL
cholesterol was calculated with the Friedewald formula and
corrected for lipoprotein(a) cholesterol.21
Fibrinogen was assayed according to the method of
Clauss.23 Blood leukocyte counts were expressed as
cellsx109/L. Endotoxin levels were measured with
commercial ELISA kits.20 Serum-soluble ICAM-1 was
determined with commercial ELISA kits (Boehringer Ingelhein
Co). All other parameters, including
microalbuminuria, 1-antitrypsin,
ceruloplasmin, C-reactive proteins, and antithrombin III, were assessed
by standard assays.20 24
Statistical Analysis
Strength and type of association between sHSP60 concentration
and 5-year progression of carotid atherosclerosis
(changes in the atherosclerosis score, size of lesions,
or intima/media thickness) were assessed using standard linear
regression analysis. Linear regression models were supplemented
by logistic regression analyses that used prevalent or incident
atherosclerosis as dichotomized outcome variables.
The test procedure was based on maximum likelihood estimators, and the
accuracy of fit of each model was assessed by the test of Hosmer and
Lemeshow.25 For ease of presentation, all
multivariate regression models were adjusted for the
same set of established and putative vascular risk factors.
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Results |
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In
33% of study subjects (n=281), serum sHSP60 was not
detectable; in others, serum levels ranged up to 11 000 ng/mL. Five
percent of subjects had concentrations >1000 ng/mL; these high
concentrations produce a maximal activation of macrophages and
endothelial cells in vitro.5 6 7 The
distribution of sHSP60 levels in the general community of Bruneck is
shown in Figure 1A
. Western blot
analysis revealed that sHSP60 was present in the
circulation as 60-kDa proteins (Figure 2).
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104 ng/mL).
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Table 1 depicts means and
SDs of selected demographic characteristics and risk factors according
to levels of sHSP60. The probability value for differences in risk
factor levels between low sHSP60 (first to fourth quintile) and high
sHSP60 (fifth quintile; levels >280 ng/mL) were derived from the
t test (unadjusted) or from ANOVA (adjusted for age and
sex). Data indicate that high sHSP60 was significantly correlated with
markers of infection and inflammation, including anti-LPS antibodies,
anti-HSP65 and anti-Chlamydia antibodies, concentrations of
circulating endotoxin, 1-antitrypsin,
C-reactive protein, ceruloplasmin, and the presence of chronic
infections, as ascertained by clinical criteria (P<0.05 to
P<0.001); however, high sHSP60 levels were not correlated
with classic risk factors for atherosclerosis, except
LDL cholesterol (apolipoprotein B) (Table 1).
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Loge-transformed serum concentrations of sHSP60
showed a significant association with prevalent carotid
atherosclerosis (odds ratios [ORs], 1.28 and 1.24 per
1-SD unit increase in sHSP60; P<0.05) and the common
carotid artery intima/media thickness (P<0.05). When sHSP60
levels were subdivided into 5 equally-spaced categories (quintiles),
the increase in atherosclerosis risk was mainly
confined to the top category (fifth quintile, >280 ng/mL) (Figure 1B
). Table 2 depicts the
associations between high sHSP60 and the various ultrasound measures of
atherosclerosis extent and progression.
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Analyses of incident atherosclerosis and
changes in the atherosclerosis score over time were
performed in light of a long-term intraindividual
consistency of sHSP60 levels (n=100; correlation
coefficient, r=0.42; P<0.0001) between sHSP60
levels from 2 independent samplings at a 5-year interval; the
coefficient 
=0.44 indicates substantial accordance in the
classification of subjects with respect to their sHSP60 level
(quintiles 1 through 4 versus quintile 5). To exclude the possible
confounding effects of vascular risk factors, multiple logistic
regression models were adjusted for the potential effects of age, sex,
smoking, alcohol consumption, hypertension, LDL and HDL
cholesterol, ferritin concentrations,
microalbuminuria, and hypothyreosis (Table 2). The
significant association between sHSP60 and
atherosclerosis applied equally to men and women,
smokers and nonsmokers, and various age groups. Finally,
analyses were virtually unchanged when systolic or
diastolic blood pressure was substituted for hypertension
(yes versus no) or apolipoproteins (AI and B) for
cholesterol fractions (LDL and HDL).
A large number of epidemiological studies reported an association
between atherosclerosis and certain persistent
bacterial and viral infections, including Chlamydia
pneumoniae and herpesviruses.26 27 28
Surprisingly, we found that anti-E. coli LPS antibody titers
were negatively correlated with incident carotid
atherosclerosis (OR, 0.85 for a 1-titer increase in
anti-LPS antibodies; P=0.03) (Figure 3), intima/media thickness (regression
coefficient, -0.017; P=0.011), and 5-year changes in the
atherosclerosis score (regression coefficient, -0.076;
P=0.02) and that these associations were independent of age,
sex, and other vascular risk predictors. Notably, low titers of
anti-LPS antibodies and high levels of sHSP60 seemed to synergistically
affect atherosclerosis risk (Figure 4). ORs of incident
atherosclerosis were 5.1 (model adjusted for age, sex,
and baseline atherosclerosis) or 6.6
(multivariate adjustment) when both conditions
coexisted in a single individual.
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Accumulating evidence supports the view that
atherosclerosis is a chronic inflammatory disease and
that infection plays an important role in this scenario.29
In this population-based prospective study, we demonstrated that
markers of inflammation (C-reactive protein or soluble ICAM-1) and the
presence of chronic infections (as ascertained by clinical criteria)
are strongly associated with the development of
atherosclerosis in the carotid arteries. The data shown
in Figure 5 indicate that the predictive
significance of sHSP60 for atherosclerosis progression
grows with laboratory and/or clinical evidence of chronic
infection/inflammation.
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Discussion |
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Data from our laboratories showed an association between serum anti-HSP65 antibodies and carotid atherosclerosis9 and the presence of T-lymphocytes specifically responding to HSP60/65 in atherosclerotic lesions.30 Other groups reported increased antibody titers in patients with atherosclerosis or coronary heart diseases,31 32 which declined after angioplasty or myocardial infarction.33 34 Recently, novel findings demonstrated that HSP60, like cytokines, stimulates the release of tumor necrosis factor-
from macrophages and the
expression of E-selectin, ICAM-1, and vascular cell adhesion molecule-1
by endothelial cells; this could lead to inflammatory
responses in the arterial wall and eventually to the
development of atherosclerosis.5 6 7 In the
present population-based study, we provide the first evidence of an
elevation of a soluble form of circulating HSP60 in subjects with
atherosclerosis. The findings provide solid evidence to
explain how HSP60 contacts vascular and immune cells and, thus, could
significantly enhance our understanding of the role of HSP60 in the
pathobiology of atherosclerosis. Proteins of the HSP60 family were previously considered to be located intracellularly in the mitochondria, where they facilitate protein translocation and act as chaperones protecting proteins from harmful enzymatic attacks during folding.1 Accumulating evidence now points to an additional surface location of HSP60 proteins on eukaryotic35 36 and even prokaryotic cells, such as H. pylori.37
In the present study, we found that sHSP60 was present in the human circulation, which tempts us to hypothesize about various possibilities resulting in HSP60 releases into the blood. First, infectious agents may be the major cause of sHSP60 release from themselves and human cells. For example, during their life cycle, chlamydiae undergo both phases of chronic, persistent, nonlytic infection, in which they remain viable but do not replicate, and phases of lytic infection.38 During these lytic phases, the host cells release both their own HSP60, which is produced during the previous chronic phase of infection, and also the chlamydial HSP60, which has been produced in the host cell in response to the infection and to previous noninfectious stimuli.39 Support for this notion is the fact that sHSP60 levels are significantly correlated with anti-Chlamydia antibodies and that both chlamydial and human HSP60s exist at high levels in human atherosclerotic lesions.5 40 Second, sHSP60 release could be from the dead cells of tissues suffering from chronic inflammation and atheroma, because several observations support the occurrence of cell death within atheroma.41 42 Our data demonstrate the correlation of sHSP60 concentrations with chronic infection and markers of inflammation. Therefore, HSP60 release into the circulation is an important event because it can then activate vascular cells and the immune system.
The second novel finding of the present study is that anti-LPS antibody titers are negatively correlated with atherosclerosis, which further supports the impact of infections. E. coli infections may result in the release of endotoxin-LPS into the circulation. LPS may stimulate the body to produce specific antibodies that will neutralize and remove LPS from the circulation. In fact, Wiedermann et al20 demonstrated that circulating endotoxin is positively correlated with atherosclerosis in this population. Thus, anti-LPS antibodies may have a protective role for the arterial wall.
In summary, we demonstrated an association between sHSP60 and atherosclerosis in the general population; this association relates to infection and inflammation. The functional role of circulating sHSP60 may involve the direct stimulation of vascular cells and the immune system, thus promoting the progression of atherosclerosis. In addition, sHSP60 could serve as a diagnostic marker for atherosclerosis risk, especially when combined with other infectious and inflammatory markers. Thus, this new approach to arterial risk assessment may be useful in the clinic.
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Acknowledgments |
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We thank Dr R.S. Gupta, Department of Biochemistry, McMaster University, Hamilton, Canada, for providing the hybridoma cell line of II-13; Dr J. Ivanyi, MRC, London, UK, for the hybridoma cell line of ML-30; Drs A. Mair, G. Rungger, and F. Spögler, Hospital of Bruneck, Italy, for help with organization; and A. Jenewein for excellent technical assistance. Supported by grants P-13099-BIO and P-12213-MED from the Austrian Science Fund. H. Perschinka is the recipient of a PhD student fellowship from the Austrian Academy of Sciences. We are grateful to the company Medac (Hamburg) for providing anti-Chlamydia and anti-H. pylori test kits.
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Footnotes |
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This article originally appeared online only with the June 6, 2000 issue of Circulation.
Received May 2, 2000; revision received May 19, 2000; accepted May 19, 2000.
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 X. Zhang, M. He, L. Cheng, Y. Chen, L. Zhou, H. Zeng, A. G. Pockley, F. B. Hu, and T. Wu Elevated Heat Shock Protein 60 Levels Are Associated With Higher Risk of Coronary Heart Disease in Chinese Circulation, December 16, 2008; 118(25): 2687 - 2693. [Abstract] [Full Text] [PDF]
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 K. Udvarnoki, L. Cervenak, K. Uray, F. Hudecz, I. Kacskovics, R. Spallek, M. Singh, G. Fust, and Z. Prohaszka Antibodies against C-Reactive Protein Cross-React with 60-Kilodalton Heat Shock Proteins Clin. Vaccine Immunol., April 1, 2007; 14(4): 335 - 341. [Abstract] [Full Text] [PDF]
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A. Shamaei-Tousi, J. P. Halcox, and B. Henderson Stressing the obvious? Cell stress and cell stress proteins in cardiovascular disease Cardiovasc Res, April 1, 2007; 74(1): 19 - 28. [Abstract] [Full Text] [PDF]
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G. Wick The Heat Is on: Heat-Shock Proteins and Atherosclerosis Circulation, August 29, 2006; 114(9): 870 - 872. [Full Text] [PDF]
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H. K. Park, E.-C. Park, S. W. Bae, M. Y. Park, S. W. Kim, H. S. Yoo, M. Tudev, Y. H. Ko, Y.-H. Choi, S. Kim, et al. Expression of Heat Shock Protein 27 in Human Atherosclerotic Plaques and Increased Plasma Level of Heat Shock Protein 27 in Patients With Acute Coronary Syndrome Circulation, August 29, 2006; 114(9): 886 - 893. [Abstract] [Full Text] [PDF]
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 B. Henderson, E. Allan, and A. R. M. Coates Stress Wars: the Direct Role of Host and Bacterial Molecular Chaperones in Bacterial Infection Infect. Immun., July 1, 2006; 74(7): 3693 - 3706. [Full Text] [PDF]
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 A. Shamaei-Tousi, J. W. Stephens, R. Bin, J. A. Cooper, A. Steptoe, A. R.M. Coates, B. Henderson, and S. E. Humphries Association between plasma levels of heat shock protein 60 and cardiovascular disease in patients with diabetes mellitus Eur. Heart J., July 1, 2006; 27(13): 1565 - 1570. [Abstract] [Full Text] [PDF]
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M. Mayr, S. Kiechl, S. Tsimikas, E. Miller, J. Sheldon, J. Willeit, J. L. Witztum, and Q. Xu Oxidized Low-Density Lipoprotein Autoantibodies, Chronic Infections, and Carotid Atherosclerosis in a Population-Based Study J. Am. Coll. Cardiol., June 20, 2006; 47(12): 2436 - 2443. [Abstract] [Full Text] [PDF]
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 L. Romics Jr, G. Szabo, J. C. Coffey, J. H. Wang, and H. P. Redmond The Emerging Role of Toll-Like Receptor Pathways in Surgical Diseases Arch Surg, June 1, 2006; 141(6): 595 - 601. [Abstract] [Full Text] [PDF]
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 K Mandal, A R Afzal, S J D Brecker, J Poloniecki, Q Xu, and M Jahangiri Association of serum soluble heat shock protein 60 with toll-like receptor 4 polymorphism and severity of coronary artery disease. Heart, May 1, 2006; 92(5): 683 - 685. [Full Text] [PDF]
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 A. Tedgui and Z. Mallat Cytokines in Atherosclerosis: Pathogenic and Regulatory Pathways Physiol Rev, April 1, 2006; 86(2): 515 - 581. [Abstract] [Full Text] [PDF]
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 A. V. Ovechkin, N. Tyagi, W. E. Rodriguez, M. R. Hayden, K. S. Moshal, and S. C. Tyagi Role of matrix metalloproteinase-9 in endothelial apoptosis in chronic heart failure in mice J Appl Physiol, December 1, 2005; 99(6): 2398 - 2405. [Abstract] [Full Text] [PDF]
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 Q. Xiao, K. Mandal, G. Schett, M. Mayr, G. Wick, F. Oberhollenzer, J. Willeit, S. Kiechl, and Q. Xu Association of Serum-Soluble Heat Shock Protein 60 With Carotid Atherosclerosis: Clinical Significance Determined in a Follow-Up Study Stroke, December 1, 2005; 36(12): 2571 - 2576. [Abstract] [Full Text] [PDF]
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 J. P.J. Halcox, J. Deanfield, A. Shamaei-Tousi, B. Henderson, A. Steptoe, A. R.M. Coates, A. Singhal, and A. Lucas Circulating Human Heat Shock Protein 60 in the Blood of Healthy Teenagers: A Novel Determinant of Endothelial Dysfunction and Early Vascular Injury? Arterioscler Thromb Vasc Biol, November 1, 2005; 25(11): e141 - e142. [Full Text] [PDF]
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 J. Wang, N. Xu, X. Feng, N. Hou, J. Zhang, X. Cheng, Y. Chen, Y. Zhang, and X. Yang Targeted Disruption of Smad4 in Cardiomyocytes Results in Cardiac Hypertrophy and Heart Failure Circ. Res., October 14, 2005; 97(8): 821 - 828. [Abstract] [Full Text] [PDF]
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A G Pockley and J Frostegard Heat shock proteins in cardiovascular disease and the prognostic value of heat shock protein related measurements Heart, September 1, 2005; 91(9): 1124 - 1126. [Abstract] [Full Text] [PDF]
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F. J. Quintana and I. R. Cohen Heat Shock Proteins as Endogenous Adjuvants in Sterile and Septic Inflammation J. Immunol., September 1, 2005; 175(5): 2777 - 2782. [Abstract] [Full Text] [PDF]
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G. Foteinos, A. R. Afzal, K. Mandal, M. Jahangiri, and Q. Xu Anti-Heat Shock Protein 60 Autoantibodies Induce Atherosclerosis in Apolipoprotein E-Deficient Mice via Endothelial Damage Circulation, August 23, 2005; 112(8): 1206 - 1213. [Abstract] [Full Text] [PDF]
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 U. Hagg, M. E. Johansson, J. Gronros, A. S. Naylor, I. H. Jonsdottir, G. Bergstrom, P.-A. Svensson, and L.-m. Gan Gene expression profile and aortic vessel distensibility in voluntarily exercised spontaneously hypertensive rats: potential role of heat shock proteins Physiol Genomics, August 11, 2005; 22(3): 319 - 326. [Abstract] [Full Text] [PDF]
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 Y. J. Woo, T. J. Grand, M. F. Berry, P. Atluri, M. A. Moise, V. M. Hsu, J. Cohen, O. Fisher, J. Burdick, M. Taylor, et al. Stromal cell-derived factor and granulocyte-monocyte colony-stimulating factor form a combined neovasculogenic therapy for ischemic cardiomyopathy J. Thorac. Cardiovasc. Surg., August 1, 2005; 130(2): 321 - 329. [Abstract] [Full Text] [PDF]
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A. Zanin-Zhorov, G. Tal, S. Shivtiel, M. Cohen, T. Lapidot, G. Nussbaum, R. Margalit, I. R. Cohen, and O. Lider Heat Shock Protein 60 Activates Cytokine-Associated Negative Regulator Suppressor of Cytokine Signaling 3 in T Cells: Effects on Signaling, Chemotaxis, and Inflammation J. Immunol., July 1, 2005; 175(1): 276 - 285. [Abstract] [Full Text] [PDF]
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K. Leineweber, P. Rohe, A. Beilfuss, C. Wolf, H. Sporkmann, H. Bruck, H.-G. Jakob, G. Heusch, T. Philipp, and O.-E. Brodde G-protein-coupled receptor kinase activity in human heart failure: Effects of {beta}-adrenoceptor blockade Cardiovasc Res, June 1, 2005; 66(3): 512 - 519. [Abstract] [Full Text] [PDF]
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M. Benagiano, M. M. D'Elios, A. Amedei, A. Azzurri, R. van der Zee, A. Ciervo, G. Rombola, S. Romagnani, A. Cassone, and G. Del Prete Human 60-kDa Heat Shock Protein Is a Target Autoantigen of T Cells Derived from Atherosclerotic Plaques J. Immunol., May 15, 2005; 174(10): 6509 - 6517. [Abstract] [Full Text] [PDF]
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 C. Carmona-Bernal, E. Quintana-Gallego, M. Villa-Gil, A. Sanchez-Armengol, A. Martinez-Martinez, and F. Capote Brain Natriuretic Peptide in Patients With Congestive Heart Failure and Central Sleep Apnea Chest, May 1, 2005; 127(5): 1667 - 1673. [Abstract] [Full Text] [PDF]
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A. Zanin-Zhorov, R. Bruck, G. Tal, S. Oren, H. Aeed, R. Hershkoviz, I. R. Cohen, and O. Lider Heat Shock Protein 60 Inhibits Th1-Mediated Hepatitis Model via Innate Regulation of Th1/Th2 Transcription Factors and Cytokines J. Immunol., March 15, 2005; 174(6): 3227 - 3236. [Abstract] [Full Text] [PDF]
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C. Banfi, V. Cavalca, F. Veglia, M. Brioschi, S. Barcella, L. Mussoni, L. Boccotti, E. Tremoli, P. Biglioli, and P. Agostoni Neurohormonal activation is associated with increased levels of plasma matrix metalloproteinase-2 in human heart failure Eur. Heart J., March 1, 2005; 26(5): 481 - 488. [Abstract] [Full Text] [PDF]
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J. L. Martin-Ventura, M. C. Duran, L. M. Blanco-Colio, O. Meilhac, A. Leclercq, J.-B. Michel, O. N. Jensen, S. Hernandez-Merida, J. Tunon, F. Vivanco, et al. Identification by a Differential Proteomic Approach of Heat Shock Protein 27 as a Potential Marker of Atherosclerosis Circulation, October 12, 2004; 110(15): 2216 - 2219. [Abstract] [Full Text] [PDF]
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P. B. Adamson, W. T. Abraham, C. Love, and D. Reynolds The evolving challenge of chronic heart failure management: A call for a new curriculum for training heart failure specialists J. Am. Coll. Cardiol., October 6, 2004; 44(7): 1354 - 1357. [Abstract] [Full Text] [PDF]
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 E. Quintana-Gallego, M. Villa-Gil, C. Carmona-Bernal, G. Botebol-Benhamou, A. Martinez-Martinez, A. Sanchez-Armengol, J. Polo-Padillo, and F. Capote Home respiratory polygraphy for diagnosis of sleep-disordered breathing in heart failure Eur. Respir. J., September 1, 2004; 24(3): 443 - 448. [Abstract] [Full Text] [PDF]
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E. Perrier, B.-G. Kerfant, N. Lalevee, P. Bideaux, M. F. Rossier, S. Richard, A. M. Gomez, and J.-P. Benitah Mineralocorticoid Receptor Antagonism Prevents the Electrical Remodeling That Precedes Cellular Hypertrophy After Myocardial Infarction Circulation, August 17, 2004; 110(7): 776 - 783. [Abstract] [Full Text] [PDF]
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 K. L. Becker, E. S. Nylen, J. C. White, B. Muller, and R. H. Snider Jr. Procalcitonin and the Calcitonin Gene Family of Peptides in Inflammation, Infection, and Sepsis: A Journey from Calcitonin Back to Its Precursors J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1512 - 1525. [Full Text] [PDF]
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 M.-F. Tsan and B. Gao Cytokine function of heat shock proteins Am J Physiol Cell Physiol, April 1, 2004; 286(4): C739 - C744. [Abstract] [Full Text] [PDF]
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B. Zal, J. C. Kaski, G. Arno, J. P. Akiyu, Q. Xu, D. Cole, M. Whelan, N. Russell, J. A. Madrigal, I. A. Dodi, et al. Heat-Shock Protein 60-Reactive CD4+CD28null T Cells in Patients With Acute Coronary Syndromes Circulation, March 16, 2004; 109(10): 1230 - 1235. [Abstract] [Full Text] [PDF]
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J. L. Wampler, K.-P. Kim, Z. Jaradat, and A. K. Bhunia Heat Shock Protein 60 Acts as a Receptor for the Listeria Adhesion Protein in Caco-2 Cells Infect. Immun., February 1, 2004; 72(2): 931 - 936. [Abstract] [Full Text] [PDF]
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K. Mattila Does periodontitis cause heart disease? Eur. Heart J., December 1, 2003; 24(23): 2079 - 2080. [Full Text] [PDF]
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P. J. Lindsberg and A. J. Grau Inflammation and Infections as Risk Factors for Ischemic Stroke Stroke, October 1, 2003; 34(10): 2518 - 2532. [Abstract] [Full Text] [PDF]
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 A. G. Pockley, A. Georgiades, T. Thulin, U. de Faire, and J. Frostegard Serum Heat Shock Protein 70 Levels Predict the Development of Atherosclerosis in Subjects With Established Hypertension Hypertension, September 1, 2003; 42(3): 235 - 238. [Abstract] [Full Text] [PDF]
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K. Node, M. Fujita, M. Kitakaze, M. Hori, and J. K. Liao Short-Term Statin Therapy Improves Cardiac Function and Symptoms in Patients With Idiopathic Dilated Cardiomyopathy Circulation, August 19, 2003; 108(7): 839 - 843. [Abstract] [Full Text] [PDF]
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L. M. Biasucci, G. Liuzzo, A. Ciervo, A. Petrucca, M. Piro, D. J. Angiolillo, F. Crea, A. Cassone, and A. Maseri Antibody Response to Chlamydial Heat Shock Protein 60 Is Strongly Associated With Acute Coronary Syndromes Circulation, June 24, 2003; 107(24): 3015 - 3017. [Abstract] [Full Text] [PDF]
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 B. Gao and M.-F. Tsan Recombinant Human Heat Shock Protein 60 Does Not Induce the Release of Tumor Necrosis Factor {alpha} from Murine Macrophages J. Biol. Chem., June 13, 2003; 278(25): 22523 - 22529. [Abstract] [Full Text] [PDF]
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J. Zhu, A. A. Quyyumi, H. Wu, G. Csako, D. Rott, A. Zalles-Ganley, J. Ogunmakinwa, J. Halcox, and S. E. Epstein Increased Serum Levels of Heat Shock Protein 70 Are Associated With Low Risk of Coronary Artery Disease Arterioscler Thromb Vasc Biol, June 1, 2003; 23(6): 1055 - 1059. [Abstract] [Full Text] [PDF]
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M. Bristow Antiadrenergic Therapy of Chronic Heart Failure: Surprises and New Opportunities Circulation, March 4, 2003; 107(8): 1100 - 1102. [Full Text] [PDF]
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S. B. Flohe, J. Bruggemann, S. Lendemans, M. Nikulina, G. Meierhoff, S. Flohe, and H. Kolb Human Heat Shock Protein 60 Induces Maturation of Dendritic Cells Versus a Th1-Promoting Phenotype J. Immunol., March 1, 2003; 170(5): 2340 - 2348. [Abstract] [Full Text] [PDF]
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 M. Bartnik, K. Malmberg, and L. Ryden Diabetes and the heart: compromised myocardial function -- a common challenge Eur. Heart J. Suppl., January 1, 2003; 5(suppl_B): B33 - B41. [Abstract] [PDF]
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A. Vink, A. H. Schoneveld, J. J. van der Meer, B. J. van Middelaar, J. P.G. Sluijter, M. B. Smeets, P. H.A. Quax, S. K. Lim, C. Borst, G. Pasterkamp, et al. In Vivo Evidence for a Role of Toll-Like Receptor 4 in the Development of Intimal Lesions Circulation, October 8, 2002; 106(15): 1985 - 1990. [Abstract] [Full Text] [PDF]
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Q. Xu Role of Heat Shock Proteins in Atherosclerosis Arterioscler Thromb Vasc Biol, October 1, 2002; 22(10): 1547 - 1559. [Abstract] [Full Text] [PDF]
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J. Lewthwaite, N. Owen, A. Coates, B. Henderson, and A. Steptoe Circulating Human Heat Shock Protein 60 in the Plasma of British Civil Servants: Relationship to Physiological and Psychosocial Stress Circulation, July 9, 2002; 106(2): 196 - 201. [Abstract] [Full Text] [PDF]
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K.C. Wollert and H. Drexler Chromogranin A in heart failure Eur. Heart J., June 2, 2002; 23(12): 926 - 927. [Full Text] [PDF]
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C. Stollberger and J. Finsterer Role of Infectious and Immune Factors in Coronary and Cerebrovascular Arteriosclerosis Clin. Vaccine Immunol., March 1, 2002; 9(2): 207 - 215. [Full Text] [PDF]
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A. G. Pockley Heat Shock Proteins, Inflammation, and Cardiovascular Disease Circulation, February 26, 2002; 105(8): 1012 - 1017. [Full Text] [PDF]
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C. Habich, K. Baumgart, H. Kolb, and V. Burkart The Receptor for Heat Shock Protein 60 on Macrophages Is Saturable, Specific, and Distinct from Receptors for Other Heat Shock Proteins J. Immunol., January 15, 2002; 168(2): 569 - 576. [Abstract] [Full Text] [PDF]
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A. Ciervo, P. Visca, A. Petrucca, L. M. Biasucci, A. Maseri, and A. Cassone Antibodies to 60-Kilodalton Heat Shock Protein and Outer Membrane Protein 2 of Chlamydia pneumoniae in Patients with Coronary Heart Disease Clin. Vaccine Immunol., January 1, 2002; 9(1): 66 - 74. [Abstract] [Full Text] [PDF]
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S. Kiechl, G. Egger, M. Mayr, C. J. Wiedermann, E. Bonora, F. Oberhollenzer, M. Muggeo, Q. Xu, G. Wick, W. Poewe, et al. Chronic Infections and the Risk of Carotid Atherosclerosis : Prospective Results From a Large Population Study Circulation, February 27, 2001; 103(8): 1064 - 1070. [Abstract] [Full Text] [PDF]
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B. Dybdahl, A. Wahba, E. Lien, T. H. Flo, A. Waage, N. Qureshi, O. F.M. Sellevold, T. Espevik, and A. Sundan Inflammatory Response After Open Heart Surgery: Release of Heat-Shock Protein 70 and Signaling Through Toll-Like Receptor-4 Circulation, February 12, 2002; 105(6): 685 - 690. [Abstract] [Full Text] [PDF]
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