scholarly journals The heart of a hibernator: EGFR and MAPK signaling in cardiac muscle during the hibernation of thirteen-lined ground squirrels, Ictidomys tridecemlineatus

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e7587 ◽  
Author(s):  
Christine L. Childers ◽  
Shannon N. Tessier ◽  
Kenneth B. Storey
Keyword(s):  
Heat Shock ◽  
Heat Shock Proteins ◽  
Cardiac Muscle ◽  
Mapk Signaling ◽  
Ground Squirrels ◽  
Caspase 9 ◽  
Protein Levels ◽  
Ictidomys Tridecemlineatus ◽  
Shock Proteins ◽  
Active Caspase

Background Thirteen-lined ground squirrels (Ictidomys tridecemlineatus) experience dramatic changes in physiological and molecular parameters during winter hibernation. Notably, these animals experience reduced blood circulation during torpor, which can put numerous stresses on their hearts. The present study evaluates the role played by the epidermal growth factor receptor (EGFR) in signal transduction during hibernation at low body temperature to evaluate signaling mechanisms. By investigating the regulation of intracellular mitogen activated protein kinase (MAPK) pathway responses, anti-apoptosis signals, downstream transcription factors, and heat shock proteins in cardiac muscle we aim to determine the correlation between upstream tyrosine phosphorylation events and downstream outcomes. Methods Protein abundance of phosphorylated EGFR, MAPKs and downstream effector proteins were quantified using immunoblotting and Luminex® multiplex assays. Results Monitoring five time points over the torpor/arousal cycle, EGFR phosphorylation on T654, Y1068, Y1086 was found to increase significantly compared with euthermic control values particularly during the arousal process from torpor, whereas phosphorylation at Y1045 was reduced during torpor. Phosphorylation of intracellular MAPK targets (p-ERK 1/2, p-JNK, p-p38) also increased strongly during the early arousal stage with p-p38 levels also rising during prolonged torpor. However, of downstream MAPK effector kinases that were measured, only p-Elk-1 levels changed showing a decrease during interbout arousal (IA). Apoptosis markers revealed a strong reduction of the pro-apoptotic p-BAD protein during entrance into torpor that remained suppressed through torpor and IA. However, active caspase-9 protein rose strongly during IA. Levels of p-AKT were suppressed during the transition phases into and out of torpor. Of four heat shock proteins assessed, only HSP27 protein levels changed significantly (a 40% decrease) during torpor. Conclusion We show evidence of EGFR phosphorylation correlating to activation of MAPK signaling and downstream p-ELK1 suppression during hibernation. We also demonstrate a reduction in p-BAD mediated pro-apoptotic signaling during hibernation with active caspase-9 protein levels increasing only during IA. I. tridecemlineatus has natural mechanisms of tissue protection during hibernation that is largely due to cellular regulation through phosphorylation-mediated signaling cascade. We identify a possible link between EGFR and MAPK signaling via p-ERK, p-p38, and p-JNK in the cardiac muscle of these hibernating mammals that correlates with an apparent reduction in caspase-9 apoptotic signaling. This reveals a piece of the mechanism behind how these mammals are resilient to cardiac stresses during hibernation that would otherwise be damaging.

scholarly journals Extracellular cell stress (heat shock) proteins—immune responses and disease: an overview

2017 ◽  
Vol 373 (1738) ◽  
pp. 20160522 ◽  
Author(s):  
A. Graham Pockley ◽  
Brian Henderson
Keyword(s):  
Heat Shock ◽  
Heat Shock Proteins ◽  
Stress Proteins ◽  
Biological Fluids ◽  
Stress Protein ◽  
Cell Stress ◽  
Immune Reactivity ◽  
Protein Levels ◽  
Shock Proteins ◽  
Adaptive Immune Systems

Extracellular cell stress proteins are highly conserved phylogenetically and have been shown to act as powerful signalling agonists and receptors for selected ligands in several different settings. They also act as immunostimulatory ‘danger signals’ for the innate and adaptive immune systems. Other studies have shown that cell stress proteins and the induction of immune reactivity to self-cell stress proteins can attenuate disease processes. Some proteins (e.g. Hsp60, Hsp70, gp96) exhibit both inflammatory and anti-inflammatory properties, depending on the context in which they encounter responding immune cells. The burgeoning literature reporting the presence of stress proteins in a range of biological fluids in healthy individuals/non-diseased settings, the association of extracellular stress protein levels with a plethora of clinical and pathological conditions and the selective expression of a membrane form of Hsp70 on cancer cells now supports the concept that extracellular cell stress proteins are involved in maintaining/regulating organismal homeostasis and in disease processes and phenotype. Cell stress proteins, therefore, form a biologically complex extracellular cell stress protein network having diverse biological, homeostatic and immunomodulatory properties, the understanding of which offers exciting opportunities for delivering novel approaches to predict, identify, diagnose, manage and treat disease. This article is part of the theme issue ‘Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective’.

scholarly journals Effects of transport stress on pathological injury and expression of main heat shock proteins in the caprine stomach

2020 ◽  
Vol 16 (1) ◽  
Author(s):  
Wei Hu ◽  
Tian Ye ◽  
Yanzhen Yang ◽  
Ben Liu ◽  
Wenya Zheng
Keyword(s):  
Heat Shock ◽  
Heat Shock Proteins ◽  
Heat Shock Protein ◽  
Jiangxi Province ◽  
Control Group ◽  
Hsp70 Mrna ◽  
Stress Group ◽  
Protein Levels ◽  
Transport Stress ◽  
Shock Proteins

Abstract Background Transportation is necessary to introduce new breeds of goats to the farm and move the adult meat goat from the farm to the slaughterhouse. However, these actions may give rise to transport stress. Heat shock proteins (HSPs) are playing some important regulate roles during transport stress. The aim of this study was to evaluate the effects of transport stress on the pathological injury and HSPs expression in the stomach of goats. A total of three batches of Ganxi goats from western Jiangxi province were enrolled in this study. For each batch, twelve healthy adult male goats were randomly divided into three groups (four goats per batch and per group): Control group, stress group transported during 2 h and stress group transported during 6 h. Results Our results showed that the different degrees of stomach walls damage, with the change of expression levels of heat shock protein 27 (HSP27), heat shock protein 70 (HSP70) and heat shock protein 90 (HSP90), occurred after goats transportation. In rumen, the mRNA and protein expressions of HSP27 and HSP70 were increased after transport stress, but not HSP90. In reticulum, all three HSPs mRNA and protein levels were upregulated after 2 h transport, but decreased after 6 h transport. In omasum, HSP27 and HSP70 mRNA and protein were increased after transport stress, however, HSP90 mRNA level only had a slightly enhancement after transport stress. In abomasum, HSP70 and HSP90 mRNA and protein levels were increased after transport stress, but HSP27 was decreased after transport stress. Conclusions Taken together, these results revealed that the pathological changes in the gastric tissues and the stomach HSPs expression in goats are related to transport stress and duration. Moreover, this study also provides some new data to advocate reducing transport stress of goats and improving animal welfare.

Effects of chronic portal hypertension on small heat-shock proteins in mesenteric arteries

2005 ◽  
Vol 288 (4) ◽  
pp. G616-G620 ◽  
Author(s):  
Xuesong Chen ◽  
Hai-Ying Zhang ◽  
Kristin Pavlish ◽  
Joseph N. Benoit
Keyword(s):  
Portal Hypertension ◽  
Heat Shock ◽  
Heat Shock Proteins ◽  
Mrna Expression ◽  
Protein Level ◽  
Small Heat Shock Proteins ◽  
Mesenteric Arteries ◽  
Protein Levels ◽  
Small Hsps ◽  
Shock Proteins

Previous studies have shown that impaired vasoconstrictor function in chronic portal hypertension is mediated via cAMP-dependent events. Recent data have implicated two small heat-shock proteins (HSP), namely HSP20 and HSP27, in the regulation of vascular tone. Phosphorylation of HSP20 is associated with vasorelaxation, whereas phosphorylation of HSP27 is associated with vasoconstriction. We hypothesized that alterations in the expression and/or phosphorylation of small HSPs may play a role in impaired vasoconstriction in portal hypertension. A rat model of prehepatic chronic portal hypertension was used. Studies were conducted in small mesenteric arteries isolated from normal and portal hypertensive rats. Protein levels of HSP20 and HSP27 were detected by Western blot analysis. Protein phosphorylation was analyzed by isoelectric focusing. HSP20 mRNA expression was determined by RT-PCR. To examine the role of cAMP in the regulation of small HSP phosphorylation and expression, we treated both normal and portal hypertensive vessels with a PKA inhibitor Rp-cAMPS. We found both an increased HSP20 phosphorylation and a decreased HPS20 protein level in portal hypertension, both of which were restored to normal by PKA inhibition. However, PKA did not change HSP20 mRNA expression. We conclude that decreased HSP20 protein level is mediated by cAMP-dependent pathway and that impaired vasoconstrictor function in portal hypertension may be partially explained by decreased expression of HSP20. We also suggest that the phosphorylation of HSP20 by PKA may alter HSP20 turnover.

Caerulein pancreatitis increases mRNA but reduces protein levels of rat pancreatic heat shock proteins

1997 ◽  
Vol 273 (4) ◽  
pp. G937-G945 ◽  
Author(s):  
M. Z. Strowski ◽  
G. Sparmann ◽  
H. Weber ◽  
F. Fiedler ◽  
H. Printz ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Proteins ◽  
Protein Expression ◽  
Mrna Levels ◽  
Protein Levels ◽  
Mediated Effects ◽  
Differential Induction ◽  
High Doses ◽  
Shock Proteins ◽  
Hsp60 Protein

We have recently reported that preconditioning through hyperthermia induces expression of pancreatic heat shock proteins (HSPs) and protects against caerulein pancreatitis. Here, we investigate caerulein-mediated effects on pancreatic HSPs without prior hyperthermia. Caerulein time and dose dependently increased pancreatic mRNA levels of the constitutive isoform of HSP70 (HSC70). However, pancreatic HSC70 protein levels were decreased, as were HSP60 protein levels. Also, in contrast to hyperthermia preconditioning, caerulein did not induce measurable levels of mRNA or protein of the inducible isoform of HSP70. Thus the pancreas reacts to different kinds of stress (hyperthermia vs. hyperstimulation) with differential induction of HSP mRNAs. Clearly, hyperthermia leads to induction of HSP protein expression, whereas caerulein treatment does not. Therefore, our current study further supports the idea that hyperthermia-induced protection against caerulein pancreatitis may be mediated through increased protein levels of pancreatic HSPs. It is further tempting to hypothesize that failure to appropriately increase HSP protein levels in response to high doses of caerulein might be a factor in the development of pancreatitis.

STAT3 and MAPK signaling maintain overexpression of heat shock proteins 90α and β in multiple myeloma cells, which critically contribute to tumor-cell survival

Blood ◽  
2006 ◽  
Vol 109 (2) ◽  
pp. 720-728 ◽  
Author(s):  
Manik Chatterjee ◽  
Sarika Jain ◽  
Thorsten Stühmer ◽  
Mindaugas Andrulis ◽  
Ute Ungethüm ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Heat Shock ◽  
Heat Shock Proteins ◽  
Cell Survival ◽  
Signaling Pathways ◽  
Target Genes ◽  
Mapk Signaling ◽  
Hsp90 Inhibition ◽  
Shock Proteins

Abstract The combined blockade of the IL-6R/STAT3 and the MAPK signaling pathways has been shown to inhibit bone marrow microenvironment (BMM)–mediated survival of multiple myeloma (MM) cells. Here, we identify the molecular chaperones heat shock proteins (Hsp) 90α and β as target genes of both pathways. The siRNA-mediated knockdown of Hsp90 or treatment with the novel Hsp90 inhibitor 17-DMAG attenuated the levels of STAT3 and phospho-ERK and decreased the viability of MM cells. Although knockdown of Hsp90β—unlike knockdown of Hsp90α—was sufficient to induce apoptosis, this effect was strongly increased when both Hsp90s were targeted, indicating a cooperation of both. Given the importance of the BMM for drug resistance and MM-cell survival, apoptosis induced by Hsp90 inhibition was not mitigated in the presence of bone marrow stromal cells, osteoclasts, or endothelial cells. These observations suggest that a positive feedback loop consisting of Hsp90α/β and major signaling pathways supports the survival of MM cells. Finally, in situ overexpression of both Hsp90 proteins was observed in most MMs but not in monoclonal gammopathy of undetermined significance (MGUS) or in normal plasma cells. Our results underpin a role for Hsp90α and β in MM pathogenesis.

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