Heat Shock Protein In Preventing Proteostasis Disease And Injury

Loss of proteostasis will lead to diseases or damages in cells,for example:Huntington's disease(HD)in human and heat stress injury in animals.Huntington's disease is one of the typical neurodegenerative diseases as a consequence of losing proteostasis.Huntington's disease is caused by the aberrant extension of CAG repeats in Huntingtin gene.When there are more than 40 CAG repeats,the Huntingtin gene coded Huntington protein(Htt)will contain a long polyglutamine fragment.Such mutant Huntingtin protein(mHtt)will be prone to aggregate,difficult to degrade and eventually break proteostasis.Thoes mHtt will accumulate in cells and form inclusions which can be as large as 2?m following is neurons disorder and death.The most common protostasis injury in amimals is heat stress injury which usually happens in breeding industrials,especially in poultry breedings.Exposing to hyperthermia can lead to multiple important organs fail,especially the heart.It was found some heat shock proteins(Hsps)can rescue Huntington's disease by helping cells to regain proteostasis.Hereby,we try to use the outcomes from the studies of human proteostasis disease to rescue proteostasis injury in animals.Heat shock protein can help to regain proteostasis and reduce heat stress injury.In this research,we tried to reduce heat stress injury in chicken myocardial cells by inducing heat shock proteins using aspirin pre-treatments.We also tried to study the mechanism of aspirin's protective functions.1 The mechanisms of Foxol prevent mHtt aggregation.This researches found Foxol can specificly reduce mHtt aggregation.The results revealed although the transcriptional inductions of several small heat shocks(sHsps)such as HspBs induced by Foxol have anti-mHtt aggregation functions,these sHsps were not activatd and expressed on protein levels.The further studies indicated that the inhibiting of mHtt aggregation caused by Foxol is independednt of any known or unknown degradation or secretory pathways.Instead,Foxo1 inhibit mHtt aggregaton by reducing mHtt synthesis by a ribosome quality control system independent manner.2 The mechanism of HspB7 preventing mHtt aggregate.This study aimed to figure out the mechanisms of mHtt aggregation inhibited by HspB7.The results indicated that the complete N-terminus of HspB7 is necessary but insufficient to prevent mHtt aggregation,a crystalline(ACD)is also required.However,as the conservatism of ACD,fusing HspB7's N-terminus with other small heat shock protein's(sHsp)ACDs also enable these fusions to inhibit mHtt aggregation.Different evidences also suggested that the N-terminus mediated co-localization between HspB7 and mHtt aggregation mediated mHtt aggregation inhibition.HspB7 preventing mHtt aggregation seems to be oligomerization/dimerization independent3 Aspirin can prevent heat stress in chicken myocardial cells in vitro and it can be related to HspB1.HspB1 can prevent heat stress myocardial cells.Aspirin(ASA)can induce HspB1 and can prevent cardiovascular disease.Therefore,we tried to prevent heat stress in jury in chicken's myocardial cells by using aspirin to induce HspB1.ELISA analysis revealed that HspB1 expression induced by ASA averaged 45.62-fold higher than that of the control.Other results indicated that the acute heat-stressed injuries were accompanied by comparatively lower HspB1 expression caused by heat stress in vitro.ASA pretreatment induced a level of HspBl presumed to be sufficient to protect myocardial cells from acute heat stress in the extracorporal model,although more detailed mechanisms will require further investigation.4 The relation between heat shock proteins and aspirin's heat stress resistance.Although aspirin prevented heat stress injury in myocardial cells,and induced HspBl,no evidence suggests inducing Hsps is responsible for protective functions yet.When HSPs were induced by aspirin,much slighter HS injury was detected.But more serious damages were observed when HSPs were suppressed by BAPTA-AM than those cells exposed to HS without BAPTA-AM,even the myocardial cells have been treated with aspirin in prior.Comparing to other HSPs,HspBl presented the largest increase after aspirin treatments,86-fold higher than the baseline(the level before HS).These findings suggested that multiple HSPs participated in aspirin's antiheat stress function but HspBl may contribute the most.5 Aspirin prevented heat stress injury in myocardial cells in vivo and it can be related to HspBl.To investigate acetyl salicylic acid(ASA)protects chicken myocardial cells in vivo from heat stress and the induction of HspB1 expression associated with anti-heat stress damage,the histopathological changes,damage-related enzyme levels,and HspB1 expression were studied in chickens after heat stress(400±1? for 0,1,2,3,5,7,10,15,or 24 h,respectively)with or without ASA administration(1 mg/kgBW,2 h prior).Myocardial cell injury was most serious in chickens exposed to heat stress without prior ASA administration,meanwhile,ASA pretreatment acted protective function against high temperature-induced injury.HspBl expression was induced under all experimental conditions but was one-fold higher in the ASA-pretreated animals(0.3138±0.0340 ng/mL)than in untreated animals(0.1437±0.0476 ng/mL)1 h after heat stress exposure,and such an increase was sustained over the length of the experiment.Our findings:indicate that pretreatment with ASA protects chicken myocardial cells from acute heat stress in vivo with almost no obvious side effects,and this protection may involve an enhancement of HspB1 expression.However,the detailed mechanisms underlying this effect require further investigation.