Induction of the 70-kDa heat shock protein (HSP70) was demonstrated immunocytochemically in adult rats 4 h to 7 days following temporary middle cerebral artery (MCA) occlusions lasting 30, 60, or 90 min. Maximal HSP70 induction occurred ∼24 h following ischemia. Thirty minutes of ischemia induced HSP70 in neurons throughout the cortex in the MCA distribution, whereas 90 min of ischemia induced HSP70 in neurons in the penumbra. HSP70 protein was induced in endothelial cells in infarcted neocortex following 60–90 min of MCA occlusion, and HSP70 was induced in endothelial cells in infarcted regions of lateral striatum following 30–90 min of MCA occlusion. hsp70 mRNA was induced in the MCA distribution in cortex and to a lesser extent in striatum at 2 h to 3 days following 60 min of ischemia. It is proposed that brief ischemia induces hsp70 mRNA and HSP70 protein in the cells most vulnerable to ischemia—the neurons. HSP70 protein is not induced in most neurons and glia following 60–90 min of ischemia in areas destined to infarct, whereas it is induced in vascular endothelial cells.
AbravayaKPhillipsBMorimotoRI. (1991) Heat shock-induced interactions of heat shock transcription factor and the human hsp70 promoter examined by in vivo footprinting. Mol Cell Biol11:586–592
2.
BarbeMFTytellMGowerDJWelchWJ. (1988) Hyperthermia protects against light damage in the rat brain retina. Science241:1817–1820
3.
BeckmannRPMizzenLAWelchWJ. (1990) Interaction of HSP70 with newly synthesized protein: Implications for protein folding and assembly. Science248:850–854
4.
BenjaminIJKrogerBWilliamsRS. (1990) Activation of the heat shock transcription factor by hypoxia in mammalian cells. Proc Natl Acad Sci USA87:6263–6267
5.
BrownIR. (1983) Hyperthermia induces the synthesis of a heat shock protein by polysomes isolated from the fetal and neonatal mammalian brain. J Neurochem40:1490–1493
6.
BrownIRRushSIvyGO. (1989) Induction of a heat shock gene at the site of tissue injury in the rat brain. Neuron2:1559–1564
7.
ChapellTWelchWSchlossmannDPalterKSchlesingerMRothmanJ, (1986) Uncoating ATPase is a member of the 70kD family of stress proteins. Cell45:3–13
8.
ChengMYHartlF-UMartinJPollockRAKalousekFNeupertWHallbergEMHallbergRLHorwichAL. (1989) Mitochondrial heat-shock protein hsp60 is essential for assembly of proteins imported into yeast mitochondria. Nature337:620–625
9.
ChiangH-LTerleckySRPlantCPDiceJF. (1989) A role for a 70-kilodalton heat shock protein in lysosomal degradation of intracellular proteins. Science246:382–385
10.
ChiricoWJWaterMGBlobelG, (1988) 70kD heat shock related proteins stimulate protein translocation into microsomes. Nature332:805–810
11.
ChoiD, (1988) Glutamate neurotoxicity and diseases of the nervous system. Neuron1:623–634
12.
ChoppMLiYDereskiOLevineSRYoshidaYGarciaJH. (1991) Neuronal injury and expression of 72-kDa heat-shock protein after forebrain ischemia in the rat. Acta Neuropathol83:66–71
13.
CurrieRWWhiteFP. (1981) Trauma-induced protein in rat tissues: A physiological role for a ‘heat shock’ protein?Science214:72–73
14.
DeshaiesRJKochBDSchenkmannR, (1989) The role of stress proteins in membrane biogenesis. Trends Biol Sci13:384–388
15.
DienelGAKiesslingMJacewiczMPulsinelliWA. (1986) Synthesis of heat shock proteins in rat brain cortex after transient ischemia. J Cereb Blood Flow Metab6:505–510
16.
DwyerBENishimuraRNBrownIR. (1989) Synthesis of the major inducible heat shock protein in rat hippocampus after neonatal hypoxia-ischemia. Exp Neurol104:28–31
17.
EllisRJ. (1987) Proteins as molecular chaperones. Nature328:378–379
18.
FerrieroDMArcaviLJSagarSMMcIntoshTKSimonRG. (1988) Selective sparing of NADPH-diaphorase neurons in neonatal hypoxia-ischemia. Ann Neurol24:670–676
19.
FerrieroDMSoberanoHQSimonRPSharpFR. (1990) Hypoxia-ischemia induces heat shock protein-like (HSP72) immunoreactivity in neonatal rat brain. Dev Brain Res53:145–150
20.
GonzalezMFShiraishiKHisanagaKSagarSMMandabachMSharpFR. (1989) Heat shock proteins as markers of neuronal injury. Mol Brain Res6:93–100
21.
GonzalezMFLowensteinDHHisanagaKSimonRPSagarSMSharpFR. (1991) Induction of heat shock protein 72-like immunoreactivity in the hippocampal formation following transient global ischemia. Brain Res Bull26:241–250
22.
GowerDJHollmanBALeeKSTytellM, (1989) Spinal cord injury and the stress protein response. J Neurosurg70:605–611
23.
HuntCMorimotoRI. (1985) Conserved features of eukaryotic hsp70 gene revealed by comparison to the nucleotide sequence of human hsp70. Proc Natl Acad Sci USA82:6455–6459
KiesslingMDanielGAJacewiczMPulsinelliWA. (1986) Protein synthesis in postischemic rat brain: A two-dimensional electrophoretic analysis. J Cereb Blood Flow Metab6:642–649
26.
KirinoTTsujitaYTamuraA, (1991) Induced tolerance to ischemia in gerbil hippocampal neurons. J Cereb Blood Flow Metab11:299–307
27.
KitagawaKMatsumotoMTagayaMHataRUedaHNiinobeMHandaNFukunagaRKimuraKMikoshibaKKamadaT, (1990) “Ischemic tolerance” phenomenon found in the brain. Brain Res528:21–24
28.
LowensteinDHSimonRPSharpFR. (1990) The pattern of 72-kDa heat shock protein-like immunoreactivity in the rat brain following fluorothyl-induced status epilepticus. Brain Res531:173–182
29.
LowensteinDHChanPHMilesMF. (1991) The stress protein response in cultured neurons: Characterization and evidence for a protective role in excitotoxicity. Neuron7:1053–1060
30.
ManzerraPBrownIR. (1990) Time course of induction of a heat shock gene (hsp70) in the rabbit cerebellum after LSD in vivo: Involvement of drug-induced hyperthermia. Neurochem Res15:53–59
31.
MariniAMKozukaMLipskyRHNowakTSJ. (1990) 70-Kilodalton heat shock protein induction in cerebellar astrocytes and cerebellar granule cells in vitro: Comparison with immunocytochemical localization after hyperthermia in vivo. J Neurochem54:1509–1516
32.
MeldrumBSEvansMCSwanJHSimonRP. (1987) Protection against hypoxic/ischemic brain damage with excitatory amino acid antagonist. Med Biol65:153–157
33.
MillerEKRaeseJDMorrison-BogoradM, (1991) Expression of heat shock protein. 70 and heat shock cognate 70 messenger RNAs in rat cortex and cerebellum after heat shock or amphetamine treatment. J Neurochem56:2060–2071
34.
MizzenLAWelchWJ. (1988) Characterization of the thermotolerant cell: I. Effects on protein synthesis activity and the regulation of heat-shock protein 70 expression. J Cell Biol106:1105–1116
35.
NagasawaHKogureK, (1989) Correlation between cerebral blood flow and histologic changes in a new rat model of middle cerebral artery occlusion. Stroke20:1037–1042
36.
NishimuraRNDwyerBEWelchWColeRde VellisJLiottaK, (1988) The induction of the major heat-stress protein in purified rat glial cells. J Neurosci Res20:12–18
37.
NishimuraRNDwyerBECleggKColeRde VellisJ, (1991) Comparison of the heat shock response in cultured cortical neurons and astrocytes. Mol Brain Res9:39–45
38.
NowakTSJr, (1985) Synthesis of a stress protein following transient ischemia in the gerbil. J Neurochem45:1635–1641
39.
NowakTSJr, (1991) Localization of 70-kDa stress protein and mRNA induction in gerbil brain after ischemia. J Cereb Blood Flow Metab11:432–439
40.
NowakTSJrBondUSchlesingerMJ. (1990) Heat shock RNA levels in brain and other tissues after hyperthermia and transient ischemia. J Neurochem54:451–458
41.
PelhamHRB. (1986) Speculations on the functions of the major heat shock and glucose-regulated proteins. Cell46:959–961
42.
RiabowolKTMizzenLAWelchWJ. (1988) Heat shock is lethal to fibroblasts microinjected with antibodies against hsp70. Science242:433–436
43.
RothmanSMOlneyJW. (1987) Excitotoxicity and the NMDA receptor. Trends Neurosci10:299–302
44.
SchallingMDagerlindABreneSHallmaHDjurfeldtMPerssonHTereniusLGoldsteinMSchlesingerDHokfeltT, (1988) Coexistence and gene expression of phenylethanolamine N-methyltransferase, and neuropeptide tyrosine in the rat and bovine adrenal gland: Effects of reserpine. Proc Natl Acad Sci USA85:8306–8310
45.
SchlesingerMJAshburnerMTissieresA, (1982) Heat shock: From Bacteria to Man. Cold Spring Harbor, Cold Spring Harbor Laboratory
46.
SharpFRLowensteinDSimonRHisanagaK, (1991a) Heat shock protein hsp 72 induction in cortical and striatal astrocytes and neurons following infarction. J Cereb Blood Flow Metab11:621–627
47.
SharpFRJasperPHallJNobleLSagarSM. (1991b) MK-801 and ketamine induce heat shock protein HSP 72 in injured neurons in posterior cingulate and retrosplenial cortex. Ann Neurol30:801–809
48.
ShiraishiKSharpFRSimonRP. (1989) Sequential metabolic changes in rat brain following middle cerebral artery occlusion: A 2-deoxyglucose study. J Cereb Blood Flow Metab9:765–773
49.
SimonRPShiraishiK, (1990) N-Methyl-d-aspartate antagonist reduces stroke size and regional glucose metabolism. Ann Neurol27:606–611
50.
SimonRPChoHGwinnRLowensteinDH. (1991) The temporal profile of 72-kDa heat shock protein expression following global ischemia. J Neurosci11:881–889
51.
SprangGKBrownIR. (1987) Selective induction of a heat shock gene in fibre tracts and cerebellar neurons of the rabbit brain detected by in situ hybridization. Mol Brain Res3:89–93
52.
SwansonRASharpFR. (1992) Zinc toxicity and induction of the 72kD heat shock protein in primary astrocyte cell culture. Glia6:198–205
53.
SwansonRAMortonMTWuGTDavidsonCSharpFR. (1990) A semiautomated method for measuring brain infarct volume. J Cereb Blood Flow Metab10:290–293
54.
ThilmannRXieYKleihuesPKiesslingM, (1986) Persistent inhibition of protein synthesis precedes delayed neuronal death in postischemic gerbil hippocampus. Acta Neuropathol71:88–91
55.
TytellMGreenbergSGLasekRJ. (1986) Heat shock-like protein is transferred from glia to axon. Brain Res363:161–164
56.
UemuraYKowallNWBealMF. (1990) Selective sparing of NADPH-diaphorase-somatostatin-neuropeptide Y neurons in ischemic gerbil striatum. Ann Neurol27:620–625
57.
UneyJBLeightPNMarsdenCDLeesAAndersonBH. (1988) Stereotaxic injection of kainic acid into the striatum of rats induces synthesis of mRNA for heat shock protein 70. FEBS Lett235:215–218
58.
VassKWelchWJNowakTSJ. (1988) Localization of 70kD stress protein induction in gerbil brain after ischemia. Acta Neuropathol77:128–135
59.
VassKBergerMLNowakTSJWelchWJLassmannH, (1989) Induction of stress protein hsp70 in nerve cells after status epilepticus in the rat. Neurosci Lett100:259–264
60.
WelchWJSuhanJP. (1986) Cellular and biochemical events in mammalian cells during and after recovery from physiological stress. J Cell Biol103:2035–2052
61.
WelshFAMoyerDJHarrisVA. (1992) Regional expression of heat shock protein-70 mRNA and c-fos mRNA following focal ischemia in rat brain. J Cereb Blood Flow Metab12:204–212
62.
WhiteFP. (1980) Differences in protein synthesized in vivo and in vitro by cells associated with the cerebral vasculature. A protein synthesized in response to trauma. Neuroscience5:1793–1799
63.
XiaoHLisJT. (1988) Germline transformation used to define key features of heat-shock response elements. Science239:1139–1142
64.
Zea LongaEWeinsteinPRCarlsonSCumminsR, (1989) Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke20:84–91
