Hsp70 mRNA induction is reduced in neurons of aged rat hippocampus after thermal stress

doi:10.1016/0197-4580(92)90088-F

Neurobiology of Aging

Volume 13, Issue 6, November–December 1992, Pages 661-672

https://doi.org/10.1016/0197-4580(92)90088-F Get rights and content

Abstract

Levels of heat-shock 70 mRNAs, relative to those of 18S rRNA, were quantitated in specific cell types of hippocampus of adult and aged rats subjected to identical heat shock regimens. Body temperature changes in response to the heat stress were no different in adult and aged rats. In control rats, as well as 3 h after initiation of heat shock in both adult and aged rats, relative levels of the constitutively synthesized heat-shock cognate 70 (hsc70) mRNA were highest in hippocampal neurons and much lower in glia. No heat-shock protein 70 (hsp70) mRNAs were present in any cell type of control adult or aged rats. In heat-shocked adult rats, the relative levels of the heat-shock-inducible hsp 70 mRNAs were highest in a subpopulation of glia, intermediate in granule cells of the dentate gyrus, and lowest in pyramidalcells of Ammon's horn. Relative levels of hsp 70 mRNA were several-fold lower in the dentate gyrus granule cells of aged rats compared to relative levels in controls and were also reduced in many pyramidal cells of the hippocampus but not in hippocampal glia. These findings suggest that some neuronal populations in the hippocampus may be at increased risk for stress-related injury in the aged animal.

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Heat shock proteins are the most evolutionarily conserved protein families induced by stressors including hyperthermia. In the context of pathologies of the male reproductive tract, cryptorchidism is the most common genital defect that compromises the reproductive potential of the male because it induces an increase in intratesticular temperature. In equine species, cryptorchidism affects almost 9 % of newborns and few studies have been carried out on the molecular aspects of the retained testis. In this study, the expression pattern of HSP60, 70, and 90 in abdominal and inguinal testes, in their contralateral descended normally testes, and in testes of normal horses were investigated by Western blot and immunohistochemistry. The histomorphological investigation of retained and scrotal testes was also investigated. The seminiferous epithelium of the retained testes showed a vacuolized appearance and displayed a completely blocked spermatogenesis for lacking meiotic and spermiogenetic cells. On the contrary, the contralateral scrotal testes did not show morphological damage and the seminiferous epithelium displayed all phases of the spermatogenetic cycle as in the normal testes. The morphology of Leydig cells was not affected by the cryptorchid state. Western blot and immunohistochemistry evidenced that equine testis (both scrotal and retained) expresses the three investigated HSPs. More in detail, the Western blot evidenced that HSP70 is the more expressed chaperone and that together with HSP90 it is highly expressed in the retained gonad (P < 0.05). The immunohistochemistry revealed the presence of the three HSPs in the spermatogonia of normal and cryptorchid testes. Spermatogonia of retained testes showed the lowest expression of HSP60 and the highest expression of HSP90. Spermatocytes, spermatids of scrotal testes, and the Sertoli cells of retained and scrotal testes did not display HSP60 whereas expressed HSP70 and HSP90. These two proteins were also localized in the nucleus of the premeiotic cells. The Leydig cells displayed the three HSPs with the higher immunostaining of HSP70 and 90 in the cryptorchid testes. The results indicate that the heat stress condition occurring in the cryptorchid testis influences the expression of HSPs.
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Citation Excerpt :
In tumor cells, the basal levels of some HSP are higher, so drugs that inhibit them are being sought for use as antitumor treatment (Albakova et al., 2020). Pardue et al. (1992) observed in aged rats subjected to hyperthermia (42 °C, 90 min) a decrease in the levels of HSP70 mRNA in the dentate gyrus granule cells and in the hippocampal pyramidal cells. In ageing, the capacity for protein homeostasis decreases as our cells and tissues grow older, leading to the accumulation of misfolded and aggregated protein species that cause dysfunction in cellular resistance by participating in aberrant interactions (Hartl, 2016).
Ageing is a multifactorial degenerative process which causes a decrease in the cellular capacity for repair and adaptation to external stressors. In this way, it is important to maintain the proper balance of the proteome. Heat shock proteins (HSP) will intervene in this balance, which are responsible for the correct assembly, folding and translocation of other proteins when cells are subjected to stressors. This type of protein is overexpressed in human tumor cells, while its deficit, both in function and quantity, contributes to ageing processes. The present work aims to analyze the response of cells from studies carried out in normal and tumor cells that are subjected to stressors.
A PubMed search was performed using the keywords “cell ageing, cell longevity, resistance, HSP, heat shock proteins, thermal shock proteins”. This search generated 212 articles. Subsequently, a series of inclusion and exclusion criteria were applied to select the articles of interest to be evaluated. Normal cells subjected to external stressors at low doses increase the number of HSP, causing them to become more resistant. In addition, tumor cells expressing high levels of HSP show greater resistance to treatment and increased cell replication. HSP intervene in the cellular resistance of both normal and tumor cells.
In the case of normal cells, the increase in HSP levels makes them respond effectively to an external stressor, increasing their resistance and not causing cell death. In the case of tumor cells, there is an increase in resistance to treatment.
Aberrant redox signalling and stress response in age-related muscle decline: Role in inter- and intra-cellular signalling
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Citation Excerpt :
Similarly, the transient decrease in protein thiol content of muscle following non-damaging contractions was mirrored in the liver following muscle contractions [114]. The HSP response occurs in a robust manner in some cell types, particularly skeletal muscle, but this response is not ubiquitously demonstrated by all cells [115,116] and those cells with a weaker response can demonstrate an increased susceptibility to cell damage and death [117,118]. Mature neurons in particular do not produce HSPs [119].
Age-associated frailty is predominantly due to loss of muscle mass and function. The loss of muscle mass is also associated with a greater loss of muscle strength, suggesting that the remaining muscle fibres are weaker than those of adults. The mechanisms by which muscle is lost with age are unclear, but in this review we aim to pull together various strands of evidence to explain how muscle contractions support proteostasis in non-muscle tissues, particularly focussed on the production and potential transfer of Heat Shock Proteins (HSPs) and how this may fail during ageing, Furthermore we will identify logical approaches, based on this hypothesis, by which muscle loss in ageing may be reduced. Skeletal muscle generates superoxide and nitric oxide at rest and this generation is increased by contractile activity. In adults, this increased generation of reactive oxygen and nitrogen species (RONS) activate redox-sensitive transcription factors such as nuclear factor κB (NFκB), activator protein-1 (AP1) and heat shock factor 1 (HSF1), resulting in increases in cytoprotective proteins such as the superoxide dismutases, catalase and heat shock proteins that prevent oxidative damage to tissues and facilitate remodelling and proteostasis in both an intra- and inter-cellular manner. During ageing, the ability of skeletal muscle from aged organisms to respond to an increase in ROS generation by increased expression of cytoprotective proteins through activation of redox-sensitive transcription factors is severely attenuated. This age-related lack of physiological adaptations to the ROS induced by contractile activity appears to contribute to a loss of ROS homeostasis, increased oxidative damage and age-related dysfunction in skeletal muscle and potentially other tissues.
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Zebrafish (Danio rerio) have been extensively utilized for understanding mechanisms of development. These studies have led to a wealth of resources including genetic tools, informational databases, and husbandry methods. In spite of all these resources, zebrafish have been underutilized for exploring pathophysiology of disease and the aging process. Zebrafish offer several advantages over mammalian models for these studies, including the ability to perform saturation mutagenesis and the capability to contain thousands of animals in a small space. In this review, we will discuss the use of mature zebrafish as an animal model. The challenges of developing and maintaining a colony of aging zebrafish will be addressed. Specific examples to support the use of mature zebrafish as an animal model will be provided including the demonstration of clinical pathology and that age-associated changes in various phenotypes can be observed in aging zebrafish.
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Heat shock proteins (HSPs) serve as molecular chaperones and endogenous cytoprotective factors. Two of the well-studied HSPs, HSP70, and HSP27 can be significantly induced in many areas of brain by a variety of stressors. A decrease in expression of brain HSPs has been documented in aged brain. Estrogen is well known as a neuroprotective hormone, and it has been reported that estrogen can regulate HSP70 and HSP27 expression in neuronal cells. In this study, the relationship between estrogen and heat stress-induced brain HSPs expression in young and aged ovariectomized (OVX) mice was investigated. Our results show that heat stress-induced levels of HSP70 proteins and mRNA transcripts was significantly lower in brain of aged (12 month) OVX mice, compared with young (2 month) OVX mice group. Estrogen supplementation (17β-estradiol 0.5 mg/kg for 7 days) restored heat stress-induced brain HSP70 expression and attenuated heat stress-induced brain DNA fragmentation, caspase 3 activation and mitochondrial leakage of cytochrome c and AIF in OVX mice. These results suggest that estrogen deficiency during aging down-regulates heat stress-induced brain HSP70 expression, which reveals a previously unknown link between estrogen deficiency and stress response elements.
Heat stress-induced heat shock protein 70 expression is dependent on ERK activation in zebrafish (Danio rerio) cells
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Heat shock response is a common event that occurs in many species. Despite its evolutionary conservation, comparative studies of heat shock response have been largely unexplored. In mammals, heat shock response decreases with age through unclear mechanisms. Understanding how the age-related decline in heat shock response occurs may provide information to understanding the biology of aging. We have previously shown that heat shock response similarly declines with age in zebrafish. However, signaling pathways that regulate the heat shock response in zebrafish are unknown. In mammals there is evidence that mitogen-activated protein kinases (MAPKs) of the ERK family alter Hsp70 transcription, serving as a potential regulator of the heat shock response. We explored if heat stress-induced Hsp70 expression is altered by activation of ERK in the zebrafish Pac2 fibroblast cell line as occurs in mammalian cells. Heat stress induced both Hsp70 mRNA expression and phosphorylation of both ERK1 and ERK2 (ERK1/2) in Pac2 cells. ERK inhibitors PD98059 and U0126 blocked both heat stress-induced and plated-derived growth factor (PDGF)-induced ERK1/2 phosphorylation, and also diminished heat-induced Hsp70 expression. Pac2 cell viability was not affected by either the ERK inhibitors or heat stress. These results demonstrate that induction of Hsp70 in response to heat stress is dependent on ERK activation in Pac2 cells. This suggests that the heat shock response in zebrafish utilizes a similar signaling pathway to that of mammals and that zebrafish are a good model for comparative studies of heat shock response.

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¹: Current address: Charter Hospital of Corona, Corona, CA 91719.

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Hsp70 mRNA induction is reduced in neurons of aged rat hippocampus after thermal stress

Abstract

Exp. Cell Res.

Mol. Brain Res.

Mech. Ageing Dev.

Neuron

Neurobiol. Aging

Anal. Biochem.

Biochem. Biophys. Res. Comm.

Trends Biochem. Sci.

Exp. Cell Res.

Neurobiol. Aging

Anal. Biochem.

Peptides

Cell

Biochem. Biophys. Res. Comm.

J. Biol. Chem.

Neuron

Neurosci. Lett.

J. Neurosci.

Biochem. Biophys. Res. Comm.

Neurobiol. Aging

Cell

Neuron

Neurosci. Lett.

J. Biol. Chem.

Brain Res.

Mol. Brain Res.

Biochim. Biophys. Acta

Mech. Ageing Dev.

FEBS Lett.

J. Biol. Chem.

Dev. Brain. Res.

Hyperthermia protects against light damage in the rat retina

Science

Interaction of hsp70 with newly synthesized proteins: Implications for protein folding and assembly

Science

Concomitant decline in heat-induced hyperthermia and HSP70 mRNA expression in aged rats

Am. J. Physiol.

Effect of hyperthermia and LSD on gene expression in the mammalian brain

Induction of heat shock (stress) genes in the mammalian brain by hyperthermia and other traumatic events: A current perspective

J. Neurosci. Res.

Expression of heat shock genes in fetal and maternal rabbit brain

Neurochem. Res.

Expression of heat shock genes (hsp70) in the mammalian brain: Distinguishing constitutively expressed and hyperthermia-inducible mRNA species

J. Neurosci. Res.

A role for the 70-kilodalton heat shock protein in lysosomal degradation of intracellular proteins

Science

Transient hyperthermia protects against subsequent forebrain ischemic cell damage in the rat

Neurology

Essential roles of 70k Da heat inducible proteins

Bioessays

Axonal transport of a clathrin uncoating ATPase (HSC70): A role for HSC70 in the modulation of coated vesicle assembly in vivo

J. Neurosci. Res.

Spinal cord lesions in heat stroke

J. Neurol. Neurosurg. Psychiatry

Astrocyte RNA in relation to neuronal RNA depletion in Alzheimer's disease

Acta Neuropathol.

Molecular chaperones

Sem. Cell Biol.

Decreased expression of heat shock protein 70 mRNA and protein after heat treatment in cells of aged rats