The temporal profile of 72-kDa heat-shock protein expression following global ischemia

185

Summary: Induction of the 70-kDa heat shock protein (HSP70) was demonstrated immunocytochemically in adult rats 4 h to 7 days following temporary middle cere bral artery (MeA) 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 MeA 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 MeA occlusion, and HSP70 was induced in endothelial cells in infarcted regions of lateral striatum following 30-90 min Normal rat brain cells do not express the 70-kDa heat shock protein (HSP70) (Vass et aI. , 1988; Brown et aI. , 1989; Gonzalez et aI. , 1989; Sharp et aI. , 1991a,b), which is a product of the hsp70 gene (Hunt and Morimoto, 1985). HSP70 is induced in brain in response to hyperthermia (Brown, 1983;Sprang and Brown, 1987; Barbe et aI. , 1988), epi lepsy (Gonzalez et aI. , 1989; Vass et aI. , 1989; Lo wenstein et aI., 1990), hypoxia-ischemia (Nowak, 1985 Kiessling et aI. , 1986; Vass et aI. , 1988; Dwy er et aI. , 1989; Gonzalez et aI., 1989; Ferriero et aI. , 1990), injection of excitotoxins (Uney et aI. , 1988; Gonzalez et aI. , 1989) 105of MeA occlusion. hsp70 mRNA was induced in the MeA distribution in cortex and to a lesser extent in stri atum 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 neu rons and glia following 60-90 min of ischemia in areas destined to infarct, whereas it is induced in vascular en dothelial cells. Key Words: Focal brain-hsp70 mRNA Middle cerebral artery-Stress and heat shock protein Stroke.1981; Brown et aI. , 1989). Gonzalez et al. (1989) emphasized the potential value of using HSP70 im munostaining as a sensitive marker of brain cell in jury.HSPs are a family of proteins that perform many functions. Some 60-to 80-kDa HSPs appear to chaperone protein movements across membranes and mediate important protein-protein interactions in normal and stressed cells (Chapell et aI. , 1986;Ellis, 1987; Chirico et aI. , 1988; Cheng et aI. , 1989; Chiang et aI. , 1989; Deshaies et aI. , 1989; Beck mann et aI. , 1990). Some 90-kDa HSPs regulate ste roid receptor availability.Once HSPs are induced, they may prevent pro teins from being denatured (Pelham, 1986) and pro tect cells from subsequent injury (Schlesinger et aI. , 1982;Johnston and Kucey, 1988; Riabowol et aI., 1988). Barbe et al. (1988) provided the first direct evidence for this protective role in the CNS by showing that preinduction in the rabbit retina via systemic hyperthermia is associated with a de crease in light-induced retinal injury. Moreover, mild global cerebral ischemia, sufficient to induce 106 H. KINOUCHI ET AL.HSP70 in the hippocampus, attenuates the hippo campal injury associated with a subsequent severe ischemic...

“…This is consistent with previous HSP70 findings following global ischemia (Gonzalez et aI. , 1991;Simon et aL 1991) and hypoxia-ischemia (Ferriero et aI. , 1990).…”

Section: Discussionsupporting

confidence: 93%

Section: This Induction In the Endothelial Cells In Infarcted Brain Rmentioning

confidence: 94%

Induction of 70-kDa Heat Shock Protein and hsp70 mRNA following Transient Focal Cerebral Ischemia in the Rat

Kinouchi

Sharp

Hill

et al. 1993

185

“…Indeed, the degree and duration of ischemia re quired to induce expression in brain remain poorly defined. In models of global ischemia, 2 min of isch emia was reported to trigger hippocampal expres sion of HSP-70 (Simon and Cho, 1990;Kirino et aI., 199 1;Nowak and Osborne, 199 1). Since ischemia for 2 min in normothermic gerbil brain is sufficient to deplete levels of ATP in most regions of hippo campus (Welsh et aI., 1990), it is apparent that even a brief period of energy failure is associated with increased expression of HSP-70.…”

Section: Discussionmentioning

confidence: 99%

Regional Expression of Heat Shock Protein-70 mRNA and c-Fos mRNA following Focal Ischemia in Rat Brain

Welsh

Moyer

Harris

1992

172

Summary: In situ hybridization was used to estimate re gional levels of heat shock protein-70 (HSP-70) mRNA and c-fos mRNA in two related models of focal cerebral ischemia. In the first model, permanent occlusion of the distal middle cerebral artery (MCA) alone caused a patchy increase in HSP-70 mRNA by 1 h in the central zone of the MCA territory of the ipsilateral neocortex. Tissue levels of HSP-70 mRNA continued to increase for several hours and remained elevated at 24 h. In contrast to the focal expression of HSP-70, c-fos mRNA was in creased throughout the ipsilateral cerebral cortex by 15 min and remained elevated for least 3 h. The wide distri bution of c-fos expression suggests it may have been caused by spreading depression. In the second model, severe focal ischemia was produced with a combination of transient (l-h) bilateral carotid artery occlusion and permanent MCA occlusion. Combined occlusion for 1 h Cerebral ischemia induces increased synthesis of a number of specific proteins, despite an overall reduction in the rate of protein synthesis (Kleihues and Hossmann, 1971; Dienel et aI., 1980 Dienel et aI., , 1986Nowak, 1985). Several of the induced proteins are members of a group of "heat shock" or "stress" proteins that are expressed in the central nervous system following a number of stresses, including heat shock (Brown and Rush, 1990), trauma (Gower et aI., 1989), as well as ischemia. Although the func tion of the stress proteins is not well understood, their induction has been correlated with increased resistance to injury in many cell types (for review, see Lindquist and Craig, 1988). In brain, induction of stress proteins prior to an episode of cerebral 204without reperfusion caused expression of HSP-70 mRNA only in regions adjacent to the central zone of the MCA territory of the neocortex. However, reperfusion of the carotids for 2 h generated intense expression of HSP-70 mRNA throughout most of the ipsilateral cerebral cortex, white matter, striatum, and hippocampus. The wide spread increase in HSP-70 mRNA suggests that reperfu sion triggered expression in all previously ischemic re gions. However, at 24 h of reperfusion, increased levels of HSP-70 mRNA were restricted primarily to the isch emic core of the neocortex. These results suggest that expression of HSP-70 mRNA is prolonged in regions un dergoing injury, but is transient in surrounding regions that recover. Key Words: Heat shock protein-70--c-fos Focal ischemia-In situ hybridization-Messenger ribo nucleic acid-Middle cerebral artery.

“…These include mem bers of the heat shock and immediate early gene (IE G) families. Focal (Gonzalez et al, 1989;Li et al, 1992;Welsh et al, 1992;Kinouchi et al, 1993a,b) and global (Vass et al, 1988;Dwyer et al, 1989;Ferriero et al, 1990;Nowak et al, 1990;Gonzalez et al, 1991;Sharp et al, 1991 a;Simon et al, 1991;Blumenfeld et al, 1992) ischemia induces the hsp70 heat shock gene in brain. Though the pre cise role of hsp70 is unknown, it is believed to bind to denatured proteins (Anathan et al, 1986;Pel ham, 1986) and to protect the cell from subsequent injury (Pelham, 1986;Barbe et al, 1988;Lowen stein et al, 1991).…”

mentioning

confidence: 99%

Induction of c-Fos, junB, c-Jun, and hsp70 mRNA in Cortex, Thalamus, Basal Ganglia, and Hippocampus following Middle Cerebral Artery Occlusion

Kinouchi

Sharp

Chan

et al. 1994

139

Middle cerebral artery (MCA) occlusion in halothane-anesthetized rats induced c-fos, junB, and c-jun immediate early gene mRNAs and hsp70 heat shock gene mRNA in brain. In situ hybridization studies showed that c-fos and junB were induced throughout all of the cortex at 1 and 4 h following MCA occlusion. hsp70 was induced in the core and margins of the MCA ischemia. By 24 h, there was little expression of c-fos, junB, c-jun, and hsp70 in the core of the MCA infarct; there was modest induction of hsp70 at the margins of the infarct; and there was diffuse induction of c-fos, junB, and c-jun in all of the cortex outside the infarct. MCA occlusion also induced these genes in subcortical structures. c-fos, junB, and hsp70 were induced in ipsilateral medial striatum, most of thalamus including medial and lateral geniculate nuclei, substantia nigra, and hippocampus. Most of these structures, except for the striatum, are not supplied by the MCA. These data show that changes in gene expression can occur in regions remote from an infarction.