The resistance to stress-induced apoptosis conferred by the thermotolerant state or by exogenous expression of HSP72 was measured in mouse embryo fibroblasts. The induction of thermotolerance protects cells from heat, tumor necrosis factor α (TNFα), and ceramide-induced apoptosis but not from ionizing radiation. Because the development of thermotolerance is associated with increased levels of heat shock proteins, we determined whether constitutive expression of one of the major inducible heat shock proteins, HSP72, could also protect cells from stress-induced apoptosis. Cells expressing constitutive HSP72 were shown to have significantly reduced levels of apoptosis after heat, TNFα, and ceramide but not after ionizing radiation. Activation of stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) was found to be strongly inhibited in thermotolerant cells after heat shock but not after other stresses. Cells that constitutively express HSP72 did not demonstrate decreased SAPK/JNK activation after any of these stresses. Thus, factors other than HSP72 that are induced in the thermotolerant state are able to reduce activation of SAPK/JNK after heat stress. Notably, the level of activation of SAPK/JNK did not correlate with the amount of apoptosis detected after different stresses. Constitutive HSP72 expression inhibited poly(ADP-ribose) polymerase cleavage in cells after heat shock and TNFα but not after ceramide or ionizing radiation. The results suggest either that SAPK/JNK activation is not required for apoptosis in mouse embryo fibroblasts or that HSP72 acts downstream of SAPK/JNK. Furthermore, the data support the concept that caspase activity, which can be down-regulated by HSP72, is a crucial step in stress-induced apoptosis. Based on data presented here and elsewhere, we propose that the heat shock protein family can be classified as a class of anti-apoptotic genes, in addition to the Bcl-2 and inhibitor of apoptosis protein families of genes.
"It has been reported that Hsp70 overexpression prevents the oxidative-stress-induced decline of mitochondrial permeability transition and the swelling of mitochondria, which may explain the role of Hsp70 in the inhibition of cell apoptosis . Other studies have suggested that Hsp70 suppresses cell apoptosis via blocking JNKs and downstream of JNK activation prior to caspase-3 activation , , . In the present study, we have demonstrated that GGA pretreatment significantly enhanced Hsp70 expression, which may account for the apoptosis resistance induced by GGA pretreatment under HHS. "
[Show abstract][Hide abstract] ABSTRACT: Increasing evidence has revealed that humid heat stress (HHS) causes considerable damage to human health. The cardiovascular system has been suggested to be the primary target of heat stress, which results in serious cardiovascular diseases. However, there is still a lack of effective approaches for the prevention and treatment of cardiovascular diseases induced by HHS.
Heat-shock proteins (Hsps), especially Hsp70, are reported to provide effective cytoprotection under various stress stimuli. In the present study, we evaluated the cytoprotective effect of geranylgeranylacetone (GGA), which was previously been reported to induce Hsp70 expression in cardiomyocytes under HHS.
Using a mouse model of HHS, we showed that the pretreatment of GGA enhanced Hsp70 expression under HHS, as examined by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. We then examined the effect of GGA pretreatment on the cardiomyocyte apoptosis induced by HHS using terminal-deoxynucleoitidyl transferase mediated nick end labeling (TUNEL) staining, and found that GGA pretreatment inhibited mitochondria-mediated apoptosis. GGA pretreatment could reverse the effect of HHS on cell apoptosis by increasing expression of Bcl-2, decreasing cytochrome c in cytosol, and increasing cytochrome c in mitochondria. However, GGA pretreatment had no effect on the oxidative stress induced by HHS as determined by levels of superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione (GSH).
We have demonstrated that GGA pretreatment suppressed HHS-induced apoptosis of cardiomyocytes through the induction of Hsp70 overexpression.
PLoS ONE 04/2014; 9(4):e93536. DOI:10.1371/journal.pone.0093536 · 3.23 Impact Factor
"While Hsp70.1 and Hsc70 were found to form insoluble structures, it remained unclear how these structures might contribute to cell survival after heat shock. As reported previously, the expression of Hsp70.1 in MEF-H2 confers an increased resistance to heat induced apoptosis compared to parental MEF, while cells rendered thermotolerant by exposure to a non-lethal heat dose were almost completely resistant to heating at 44°C for 20 minutes (Fig. 4A) . The kinetics of heat induced apoptosis revealed a highly regulated process, with apoptosis in MEF first detected at 6–8 hours after heating and almost all cells fated to undergo apoptosis having completed the process by 12 hours (Fig. 4B). "
[Show abstract][Hide abstract] ABSTRACT: Heat induces Hsp70.1 (HSPA1) and Hsc70 (HSPA8) to form complex detergent insoluble cytoplasmic and nuclear structures that are distinct from the cytoskeleton and internal cell membranes. These novel structures have not been observed by earlier immunofluorescence studies as they are obscured by the abundance of soluble Hsp70.1/Hsc70 present in cells. While resistant to detergents, these Hsp70 structures display complex intracellular dynamics and are efficiently disaggregated by ATP, indicating that this pool of Hsp70.1/Hsc70 retains native function and regulation. Hsp70.1 promotes the repair of proteotoxic damage and cell survival after stress. In heated fibroblasts expressing Hsp70.1, Hsp70.1 and Hsc70 complexes are efficiently disaggregated before the cells undergo-heat induced apoptosis. In the absence of Hsp70.1, fibroblasts have increased rates of heat-induced apoptosis and maintain stable insoluble Hsc70 structures. The differences in the intracellular distribution of Hsp70.1 and Hsc70, combined with the ability of Hsp70.1, but not Hsc70, to promote the disaggregation of insoluble Hsp70.1/Hsc70 complexes, indicate that these two closely related proteins perform distinctly different cellular functions in heated cells.
PLoS ONE 12/2012; 7(12):e52351. DOI:10.1371/journal.pone.0052351 · 3.23 Impact Factor
"ther stress conditions , such as the presence of free oxygen radicals , infections , heavy metals , ethanol and ischaemia ( Lind - quist 1986 ; Welch 1992 ) . Increased HSP70 expression is associated with increased ability of the stressed cells to protect themselves from cell death ( Mosser et al . 1997 ) by interacting with apoptotic mechanisms ( Buzzard et al . 1998 ; Li et al . 2000 ; Parcellier et al . 2003 ) . Under heat stress conditions , they have shown to activate transcription and production of HSP genes and to modify maternal hormones and uterine environment ( Ju 2005 ) . Specifically , mRNA expression of HSP70 has been reported to correlate with the length of heat shock to induce thermoto"
[Show abstract][Hide abstract] ABSTRACT: We examined the effect of prolonged high heat stress on reproductive performance and its relationship with gene expression in pre-implantation embryos and endometrial tissue. In experiment 1, primiparous rabbit does were divided into two environments: control does (maintained between 14 and 22°C) and heat-treated does housed in a climatic chamber (maintained between 25 and 35°C). Females were reproducing, and the litter size and live born kits were assessed at 2nd and 3rd partum. In heat-treated does, lower litter size (9.7 ± 0.48 and 11.4 ± 0.50) and fewer live born kits (7.2 ± 0.55 and 10.2 ± 0.57) were observed, although similar ovulation rates and numbers of pre-implantation embryos were noted. In experiment 2, after 3rd partum multiparous non-lactating does from each experimental group were used to obtain pre-implantation embryos and endometrial tissue. mRNA transcripts from OCT-4, VEGF, erbB3, Ifn-ɣ, HSP70 and HSP90 were analysed by real-time qPCR. Higher values of OCT-4 expression were observed in embryos and endometrial tissue in females reproduced under heat conditions. Moreover, elevated temperatures have been shown to up-regulate VEGF in embryos and down-regulate Ifn-ɣ in endometrial tissue. The findings suggest a deleterious temperature effect on litter size and live born kits as a consequence of variation in gene expression pattern of the pre-implantational embryo and the endometrium associated with proliferation and differentiation and probably with implantation and uterine and foetal development during gestation.
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