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PubMed2006

Heat shock proteins: endogenous modulators of apoptotic cell death.

The highly conserved heat shock proteins (Hsps) accumulate in cells exposed to heat and a variety of other stressful stimuli. Hsps, that function mainly as molecular chaperones, allow cells to adapt to gradual changes in their environment and to survive in otherwise lethal conditions. The events of cell stress and cell death are linked and Hsps induced in response to stress appear to function at key regulatory points in the control of apoptosis. Hsps include anti-apoptotic and pro-apoptotic proteins that interact with a variety of cellular proteins involved in apoptosis. Their expression level can determine the fate of the cell in response to a death stimulus, and apoptosis-inhibitory Hsps, in particular Hsp27 and Hsp70, may participate in carcinogenesis. This review summarizes the apoptosis-regulatory function of Hsps.

Animals↗

PubMed2003

Proteins involved in salvage of the myocardium.

In the Western world, cardiac ischemic disease is still the most common cause of death despite significant improvements of therapeutic drugs and interventions. The fact that the heart possesses an intrinsic protection mechanism has been systematically overlooked before the 1980s. It has been clearly shown that the activation of this mechanism can reduce the infarct size after an ischemic insult. Prerequisite is the induction of the synthesis of such cardio-protective proteins as heat shock proteins (HSPs) and anti-oxidative enzymes. HSPs are involved in the maintenance of cell homeostasis by guiding the synthesis, folding and degradation of proteins. Besides, the various family members cover a broad spectrum of anti-oxidative, anti-apoptotic and anti-inflammatory activities. Although the major inducible HSP72 has received most attention, other HSPs are able to confer cardioprotection as well. In addition, it seems that there is a concerted action between the various cardio-protective proteins. One drawback is that the beneficial effects of HSPs seem to be less effective in the compromised than in the normal heart. Although clinical studies have shown that there is a therapeutic potential for HSPs in the compromised heart, major efforts are needed to fully understand the role of HSPs in these hearts and to find a safe and convenient way to activate these protective proteins.

Animals↗

PubMed1995

Cell stress and implications of the heat-shock response in skin.

Heat-shock proteins (HSPs), or so-called 'stress proteins' may play an important role in cutaneous pathophysiology. HSPs are a group of highly conserved molecules that are expressed by all cells when subjected to heat or other forms of physical or chemical stress. The physiological roles of stress proteins are varied and are important in stress and nonstress conditions. They bind to other cellular proteins and participate in protein folding pathways during stress and also during the synthesis of new polypeptides. HSPs are also essential for thermotolerance and for prevention and repair of damage caused in DNA after ultraviolet exposure. Although HSPs are expressed in the skin in both epidermis and dermis, HSPs may influence many other cellular processes in the inflammatory and immune skin response. Many authors have speculated on a link between HSPs and human skin disease characterized by inflammation and proliferation.

Heat-Shock Proteins↗

PubMed1992

Are heat shock proteins involved in autoimmunity?

Heat shock proteins (HSPs) have been postulated to be critical antigens in both autoimmune disease and experimental models of autoimmunity. This postulate has been largely based on the remarkable conservation of aminoacid sequence between human and bacterial HSPs, so that it has been argued that immune responses initially directed against the HSP of an infectious agent, would have the potential to initiate or maintain autoimmune disease. This would apply especially to T cell recognition of HSPs, since the T cell focuses on short peptide epitopes within a protein antigen rather than on the antigen's secondary structure. This article critically evaluates the available experimental evidence relating to this hypothesis: although research has clearly highlighted the central role of HSPs in the cellular immune response to pathogenic organisms and has shown the potential for T cell responses directed against self HSPs, a role for self HSPs as major target antigens in autoimmune disease has yet to be firmly established.

Animals↗

PubMedDate not supplied

Stressor-specific induction of heat shock proteins in rat hepatoma cells.

In order to determine whether induction of specific stress proteins is dependent on a given stressor and whether induction of these proteins is linked to survival, Reuber H35 rat hepatoma cells were exposed to five different environmental stressors (heat shock, arsenite, cadmium, dinitrophenol and ethanol). The effect of these stressors was studied on cell survival as well as on inhibition and recovery of protein synthesis and on induction of heat shock proteins (hsps). In this article, we present evidence that several well-known hsp-inducers fail to stimulate specific hsps in a degree that is comparable to the induction of these hsps by heat shock. Most evidently, hsp60 is not induced by cadmium-treatment, whereas hsp100 is hardly induced by sodium arsenite. Treatment with DNP only slightly induces hsp68 and hsp84, whereas no detectable induction of hsps is observed after treatment with ethanol. In contrast, treatment with cadmium raises the amount of hsp28 to a higher level as compared to heat shock. A comparison of the stressor-specific induction of major hsps was also made under conditions of similar impact on cellular physiology: (a) stressor conditions up to the critical point that cell death starts to occur, and (b) conditions of iso-survival (50%). We conclude that hsps cannot be simply used as a general risk-assessment tool, and that the validation of stressor-specific risk-assessment warrants further research with larger groups of proteins.

Animals↗

PubMed2005

Heat shock proteins in vascular disease--a review.

INTRODUCTION: There is growing evidence that heat shock proteins (HSPs), a family of stress-inducible proteins may be involved in the pathogenesis of atherosclerotic vascular diseases. Here, we systematically review the evidence behind this notion. METHODS: A detailed literature search and extensive bibliographic review of literature relating to HSPs and atherosclerotic vascular disease. RESULTS: Atherosclerotic vascular disease is classified into four main areas of presentation: carotid, coronary, aortic and peripheral vascular disease, for consideration in this review. In each of these vascular diseases, the evidence linking HSPs and atherosclerosis is outlined in a systematic manner. Current evidence suggests that components of the immune system may be involved in the pathogenesis of atherosclerosis, with HSPs acting as auto-antigens in the immune response. HSPs are detected in atherosclerotic lesions and antibodies to HSPs are increased in patients with vascular disease; the rise often correlating with the severity of atherosclerosis. The levels of anti-HSP antibodies have been shown to be independent predictors of risk and have prognostic value. CONCLUSION: There is a strong link between heat shock protein expression and the principal manifestations of atherosclerotic vascular diseases. A better understanding of this involvement could lead to the development of new and improved treatment strategies.

Aortic Diseases↗

PubMed2004

Heat shock proteins can protect aged human and rodent cells from different stressful stimuli.

Heat shock proteins (hsps) are induced by stressful stimuli and have been shown to protect cells and organs from such stresses both in vitro and in vivo. Because of this, mildly stressful stimuli, sufficient to induce hsp over-expression can protect against a subsequent more severe stress. In cells from aged individuals, however, no hsp induction is observed upon exposure to stress and no protective effect of a mild stress is observed. Here, we show that bypassing the block to hsp induction by artificially over-expressing hsps, can produce a protective effect against a variety of damaging stimuli in cells from aged rats or aged humans, indicating that hsps can have a protective effect in aged cells, provided successful over-expression can be achieved. Hence, hsps over-expression could be of therapeutic benefit in aged individuals if procedures to over-express the hsps can be developed either by devising non-stressful procedures to induce endogenous hsp over-expression or by developing vectors able to efficiently deliver exogenous hsps.

Adult↗

PubMed2007

Differential expression of heat shock protein mRNAs under in vivo glutathione depletion in the mouse retina.

Heat shock proteins (HSPs) are highly conserved proteins playing a protective role under deleterious conditions caused by a wide variety of pathophysiological, including environmental stresses. Glutathione (GSH) is known to play a critical role in the cellular defense against unregulated oxidative stress in mammalian cells including neurons. We previously demonstrated that GSH depletion induced cell death in the retina, but the mechanism(s) of cellular protection were not clear. Unregulated oxidative stress was induced by depletion of intracellular GSH by systematic administration of buthionine sulphoximine (BSO), an inhibitor of gamma-glutamylcysteine synthetase. After 0, 1, 4 and 7 days of BSO administration, we examined expression of both large and small HSP mRNAs (hsp90alpha, hsp90beta, hsp70, hsp60 and hsp25) in oxidative-stressed mouse retina. Of large HSPs, only hsp70 expression was significantly decreased from 1 day after BSO injection, whereas expression of other large hsps was not changed on day 1. Expression of hsp60 decreased on 4 days, whereas expression of hsp90 decreased on 7 days after BSO administration. Different from large HSPs, a small HSP, hsp25 increased its expression to a great extent from 1 day after BSO administration. Taken together, our results show that unregulated oxidative stress could induce differential expression of HSPs, which, in turn, may play distinct roles in the cellular defense. Targeting HSPs, therefore, may provide novel tools for treatment of retinal degenerative diseases such as glaucoma, retinopathy or age-related macular degeneration.

Animals↗

PubMed2004

Purification of recombinant and endogenous HSP70s.

Heat shock proteins (HSPs) are powerful immunogens against the antigenic peptides they chaperone. The antigenic peptides are MHC I-binding peptides and their elongated precursors derived from tumor antigens, viral antigens, minor histocompatibility antigens, or model antigens. HSP-peptide complexes can immunize against tumors and pathogen-infected cells. Remarkably, HSPs do not immunize after elution of the peptides they chaperone, demonstrating that HSPs are not immunogenic per se, whereas HSP-peptide complexes are. Additionally, HSPs activate professional antigen presenting cells (APC) through specific receptor(s) to stimulate secretion of pro-inflammatory cytokines, up-regulation of co-stimulatory molecules and activation of dendritic cells. The mechanistic exploration of the role of the HSPs on the innate and adaptive component of the immune system requires their isolation in large quantity. On one hand, isolation of naturally formed HSP-peptide complexes is key to study their specific immunogenicity. On the other hand, purification of HSPs free of endotoxin contamination is an absolute requirement for the analysis of their ability to activate APC in vitro. This chapter describes a convenient and fast method of purification of endogenous and recombinant HSP of 70 kDa (HSP70) that addresses these two considerations.

Animals↗

PubMed1996

Heat shock response of Trichinella spiralis and T. pseudospiralis.

Heat shock proteins (HSPs) were documented for the first time in both somatic extracts and excretory/secretory (ES) products of the infective-stage larvae of Trichinella spiralis and T. pseudospiralis. Larvae recovered from muscles of infected mice were heat shocked at 37, 40, 43 and 45 degrees C in RPMI 1640 medium containing L(-)[35S]methionine. Somatic extracts and ES products of heat-shocked worms were then analysed by SDS-PAGE, autoradiography and laser densitometry. Prominent bands of HSPs were observed at 43 degrees C which is the optimal heat shock temperature. The major HSPs in somatic extracts of T. spiralis were 20, 47, 50, 70, 80 and 86 kDa. When the temperature was increased from 37 to 43 degrees C, the greatest increase in absorbance was observed in HSPs 70 and 86. In vitro translation of mRNA in a nuclease-treated rabbit reticulocyte lysate system showed an increase in the synthesis of the 80 kDa protein. This suggests that the production of HSP 80 is regulated at the transcriptional level. The major HSPs in the ES products were 11, 45, 53 and 64 kDa. In T. pseudospiralis, the major HSPs in the somatic extracts were 20, 26, 31, 50, 53, 70, 80 and 86 kDa, and in the ES products, 11, 35, 37, 41 and 64 kDa.

Animals↗

PubMedDate not supplied

Extractive cultivation of recombinant Escherichia coli using aqueous two-phase systems for production and separation of intracellular heat shock proteins.

The extractive cultivation of recombinant Escherichia coli cells to produce, release, and separate heat shock proteins (HSPs; GroEL and GroES) using poly(ethylene glycol) (PEG)/dextran (Dex) aqueous two-phase systems was developed. The growth rate of E. coli OW10/pND5 cells in the PEG/Dex two-phase media was almost the same value as that in the control media. The addition of 0.1 M potassium phosphate salts (KPi) increased the productivity of HSPs with keeping the growth rate of E. coli cells relatively high. The partition coefficients of HSPs were improved to greater values when phosphate salts were added at a concentration of more than 0.1 M. As a result, PEG/Dex systems supplemented with 0.1 M KPi were found to be the optimized two-phase systems for the extractive cultivation of E. coli cells. In the systems, the HSPs were selectively partitioned to the top phase while cells occupied the bottom phase and the interface between the two phases. This integrated process was extended to a semicontinuous operating mode, where the top phase containing the HSPs was recovered following intermittent heating and ultrasonic irradiation. The bottom phase containing cells and cell debris was recycled together with new top phase solution to repeat production and recovery of HSPs.

Culture Media↗

PubMed1999

Treatment with 24-epibrassinolide, a brassinosteroid, increases the basic thermotolerance of Brassica napus and tomato seedlings.

Brassinosteroids are plant growth-promoting compounds that exhibit structural similarities to animal steroid hormones. Recent studies have indicated that brassinosteroids are essential for proper plant development. In addition to a role in development, several lines of evidence suggest that brassinosteroids exert anti-stress effects on plants. However, the mechanism by which they modulate plant stress responses is not understood. We show here that Brassica napus and tomato seedlings grown in the presence of 24-epibrassinolide (EBR) are significantly more tolerant to a lethal heat treatment than are control seedlings grown in the absence of the compound. Since a preconditioning treatment of seedlings was not required to observe this effect, we conclude that EBR treatment increases the basic thermotolerance of seedlings. An analysis of heat shock proteins (HSPs) in B. napus seedlings by western blot analysis indicated that the HSPs did not preferentially accumulate in EBR-treated seedlings at the control temperature. However, after heat stress, HSP accumulation was higher in EBR-treated than in untreated seedlings. The results of the present study provide the first direct evidence for EBR-induced expression of HSPs. The higher accumulation of HSPs in EBR-treated seedlings raises the possibility that HSPs contribute, at least in part, to thermotolerance in EBR-treated seedlings. A search for factors other than HSPs, which may directly or indirectly contribute to brassinosteroid-mediated increase in thermotolerance, is underway.

Adaptation, Physiological↗

PubMedDate not supplied

In situ expression of heat shock proteins, Hsc73, Hsj2 and Hsp86 in the developing tooth germ of mouse lower first molar.

This study examined the detailed gene expression pattern of three different heat shock proteins (HSPs), Hsc73, Hsj2, and Hsp86, by means of an in situ hybridization method. Hsc73, Hsj2, and Hsp86 were shown in our previous study to be differentially expressed in the mouse embryonic mandible at day 10.5 (E10.5) gestational age. These HSP genes showed similar expression patterns during development of the mouse lower first molar. HSPs-expressing cells were widely distributed in both the epithelial and underlying ectomesenchymal cells at E10.5, and then were slightly localized at E12 in an area where the tooth germ of the lower first molar is estimated to be formed. A strong expression of HSPs was observed in the tooth germ at E13.5. At the cap stage, HSPs were expressed in the enamel organ and dental papilla. At the bell stage, HSPs were distinctly expressed in the inner enamel epithelium and dental papilla cells facing the inner enamel epithelial layer, which later differentiate into ameloblasts and odontoblasts, respectively. This study is the first report in which Hsc73, Hsj2, and Hsp86 were distinctly expressed in the developing tooth germ, thus suggesting these HSPs are related to the development and differentiation of odontogenic cells.

Animals↗

PubMed1990

Ribosomes as sensors of heat and cold shock in Escherichia coli.

Nearly all cells respond to an increase in temperature by inducing a set of proteins, called heat shock proteins (HSPs). Because a large number of other stress conditions induce the HSPs (or at least the most abundant ones), this response is often termed the universal stress response. However, a careful study of conditions that truly mimic a temperature shift suggested that these proteins are induced in response to a change in the translational capacity of the cell. To test this directly, Escherichia coli cells were treated with antibiotics that target the prokaryotic ribosome. Two-dimensional gels were used to evaluate the ability of these drugs to alter the rate of synthesis of the HSPs. One group of antibiotics induced the HSPs, whereas a second group repressed the HSPs and induced another set of proteins normally induced in response to a cold shock. Depending on the concentration used, the induction of the heat or cold shock proteins mimicked a mild or severe temperature shift. In addition, antibiotics of the cold shock-inducing group were found to block high temperature induction of the HSPs. The results implicate the ribosome as a prokaryotic sensor for the heat and cold shock response networks, a role it may serve in eukaryotes as well.

Anti-Bacterial Agents↗

PubMed1998

Stress protein expression in rat liver during tumour promotion: induction of heat-shock protein 27 in hepatocytes exposed to 2-acetylaminofluorene.

Exposure of cells to a variety of stresses such as heat, radiation and xenobiotics leads to increased expression of heat-shock proteins (HSPs). HSPs protect cells against irreversible protein damage and are involved in adaptive responses to stress stimuli. Some HSPs are overexpressed in neoplasias, possibly contributing to the increased drug tolerance often observed in such lesions. We have studied HSP expression in two experimental rat hepatocarcinogenesis models. Our aim was to clarify whether they are involved in stress adaptation in hepatocytes during carcinogen exposure, and whether HSPs may contribute to xenobiotic resistance in preneoplastic lesions. The complete carcinogen 2-acetylaminofluorene (AAF) was used in a continuous feeding protocol, and in the resistant hepatocyte model where the growth of diethylnitrosamine initiated lesions is efficiently promoted. Of the HSPs tested, only heat-shock protein 27 (hsp27) was induced during continuous AAF exposure. After 4 weeks of feeding AAF, increased hsp27 expression was noted in hepatocytes in perivenous areas of the liver lobule, possibly mediating an adaptive response to stress caused by reactive AAF metabolites. Enzyme altered preneoplastic foci were not found to overexpress HSPs. Thus, HSP induction does not seem to be a general mechanism underlying the increased stress tolerance observed in such lesions.

2-Acetylaminofluorene↗

PubMed1997

Heat shock protein induction protects human respiratory epithelium against nitric oxide-mediated cytotoxicity.

Induction of heat shock proteins (HSPs) confers protection against a variety of cytotoxic agents. We hypothesized that induction of HSPs would protect cultured human respiratory epithelium against nitric oxide (NO)-mediated injury. Incubation of a human bronchial epithelial cell line (BEAS-2B cells) at 43 degrees C for 1.5 h induced expression of several HSPs. Prior induction of HSPs was associated with protection against the NO-donors S-nitroso-N-acetyl penicillamine and 3-morpholinsydnonimine. Protection was evident as improved short term survival and improved ability of cells to recover and proliferate after exposure to NO. Prior induction of HSPs also attenuated NO-mediated decreases in cellular ATP levels, but did not decrease nitrotyrosine formation. Specific overexpression of HSP-70 by plasmid-directed gene transfer protected murine respiratory epithelial cells against S-nitroso-N-acetyl penicillamine. We conclude that in cultured human respiratory epithelium induction of HSPs confers protection against NO-mediated cytotoxicity, possibly by preservation of cellular energetics. We also suggest that HSP-70 may play a specific role in protection.

Adenosine Triphosphate↗

PubMed1999

Heat shock proteins: facts, thoughts, and dreams.

The most primitive mechanism of cellular protection involves the expression of a polypeptide family named heat shock or stress proteins (hsps). Some of these hsps are present in unstressed cells and play an important role in the folding and translocation of polypeptides across membranes. Thus, they have been termed molecular chaperones. Hsps are expressed in response to an array of stresses, including hyperthermia, oxygen radicals, heavy metals, ethanol, and amino acid analogues. In addition, the heat shock response is induced during clinically relevant situations such as ischemia/reperfusion and circulatory and hemorrhagic shock. All of the above stresses have in common that they disturb the tertiary structure of proteins and have adverse effects on cellular metabolism. Pretreatment of cells with a mild stress, sufficient to induce the expression of hsps, results in protection to subsequent insults. This phenomenon has been coined "stress tolerance" and is apparently caused by the resolubilization of proteins that were denatured during the stress. In addition, cellular structures (microfilaments and centrosomes) and processes (transcription, splicing, and translation) are stabilized or repaired during a second stress in stress tolerant cells and organisms. There is a great body of evidence indicating a direct role of hsps in the stabilization of these events. The intrinsic capacity of hsps to protect cells has potential relevance as a natural mechanism of organ protection during harmful environmental conditions and operative procedures, and in the combat against pathogens.

Animals↗

PubMed2006

Expression and prognostic examination of heat shock proteins (HSP 27, HSP 70, and HSP 90) in medulloblastoma.

Expression of heat shock proteins (HSPs) is of prognostic significance in several tumor types. HSP expression levels were determined in medulloblastomas and tested whether HSPs expression was associated with prognostic parameters. Expression of antiapoptotic HSP 27, HSP 70, and HSP 90 was investigated by immunohistochemistry, on paraffin-embedded sections from 65 patients. Expression of HSPs was validated on internal vascular controls and by Western blotting analysis. Sample evaluation was based on the estimated percentage of HSP positive tumor cells. For survival analysis Kaplan-Meier method, for statistical analysis chi2 test, univariate analysis, and log rank test were applied. Expression of HSPs varied in medulloblastomas. On the basis of the average expression rate of HSPs, at HSP 27 and HSP 90 with a 10% cut off, and at HSP 70 with a 70% cut off 2 groups were created. The amount of expression of any of the HSP types was not significantly associated with known prognostic factors (age of patient, extent of resection, presence of metastasis) and histologic subtype. After an average follow-up period of 4.30 years, no significant difference was observed in survival depending on the expression of HSP 27 or HSP 70 or HSP 90. The high expression of HSPs indicates that these proteins are potential therapeutic targets.

Adolescent↗