Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Heat shock protein 72 (HSP72) is a stress-inducible protein capable of protecting a variety of cells from toxins, thermal stress, and ischemic injury. The cytoprotective role and mechanism of action of HSP72 in renal cell ischemic injury remain unclear. To study this, HSP72 was introduced (liposomal transfer) or induced (thermal stress, 43 degrees Cx1 hour) in renal tubular cells (LLC-PK1) with Western blot confirmation. Cells were subjected to simulated ischemia 24 hours after liposomal HSP72 transfer or thermal stress, and the effect of HSP72 on nuclear factor-kappaB (NF-kappaB) activation (electrophoretic mobility shift assay and immunohistochemistry), IkappaBalpha production (Western blot), postischemic tumor necrosis factor-alpha (TNF-alpha) production (RT-PCR), and apoptosis (TUNEL assay) were determined. In separate experiments, the role of TNF-alpha in apoptosis was determined (anti-TNF-alpha neutralizing antibody). Results demonstrated that both liposomal transfer of HSP72 and thermal induction of HSP72 prevented NF-kappaB activation and translocation, TNF-alpha gene transcription, and subsequent ischemia-induced renal tubular cell apoptosis. Furthermore, TNF-alpha neutralization also inhibited ischemia-induced renal tubular cell apoptosis. These results indicate that liposomal delivery of HSP72 inhibits ischemia-induced renal tubular cell apoptosis by preventing NF-kappaB activation and subsequent TNF-alpha production. Further elucidation of the mechanisms of HSP-induced cytoprotection may result in therapeutic strategies that limit or prevent ischemia-induced renal damage.
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PMID:Liposomal delivery of heat shock protein 72 into renal tubular cells blocks nuclear factor-kappaB activation, tumor necrosis factor-alpha production, and subsequent ischemia-induced apoptosis. 1259 41

Diabetes and nitric oxide synthase (NOS) inhibition both exacerbate mesenteric ischemia/ reperfusion injury. Heat shock protein 72 (HSP-72) protects against KDa ischemia/reperfusion damage in vivo. The effect of diabetes on HSP-72 expression in vivo is unknown. The aim of this study was to determine the effects of diabetes and NOS inhibition on HSP-72 induction in vivo. Rats were assigned to four groups: control (C), streptozotocin-induced diabetic (D), acute hyperglycemia (A), and L-N(omega)-nitro-L-arginine treated (L). Rats were subjected to hyperthermia and allowed to recover for 4 hours. Intestine and liver samples from heated (H) and nonheated (NH) rats were analyzed for HSP-72 by Western blot. HSP-72 levels were increased significantly in CH compared to CNH rats. No deaths occurred in CH rats; however, death rates were significant in AH, DH, and LH rats. DH rats died earlier than LH and AH rats. HSP-72 in liver and intestine was reduced significantly in LH rats. When compared with CH rats the surviving AH and DH rats exhibited similar HSP-72 levels in the liver. Diabetes, acute hyperglycemia, and L-N(omega)-nitro-L-arginine treatment lower heat stress tolerance. NOS is required for HSP-72 expression, but not survival. Diabetics who survive heat stress moderately express HSP-72. Characterization of altered thermotolerance and HSP-72 may provide mechanisms for the deranged diabetic stress response.
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PMID:Effect of hyperglycemia and nitric oxide synthase inhibition on heat tolerance and induction of heat shock protein 72 kDa in vivo. 1288 22

The present study shows that anoxic neuronal depolarization or NMDA receptor activation are potent stimuli for inducing spinal neuronal heat shock protein 70 (Hsp70). Spinal hyperthermia, despite its significant glutamate releasing effect, induced only glial Hsp70 upregulation. No significant increase in spinal Hsp70 expression after potassium depolarization was seen. Transient spinal ischemia (6 min) was induced by the inflation of a 2F Fogarty catheter placed into descending thoracic aorta during concurrent hypotension (40 mmHg). To determine the onset of anoxic depolarization extracellular concentration of K+ was measured in the lumbar dorsal horn using a microelectrode. Spinal hyperthermia (42 degrees C) or hypothermia (27 degrees C) was induced using a heat exchanger placed in the paravertebral subcutaneous space overlying Th5-S4 spinal segments. To measure extracellular concentration of glutamate during hyperthermia a loop dialysis catheter was implanted into lumbar intrathecal space. Receptor specific (NMDA, 3 microg) or non-specific (KCl, 10 microl, 1M) neuronal depolarization was induced using previously implanted intrathecal catheters. After ischemia, temperature manipulations or drug injections animals survived for 4 or 24h. Animals were then terminally anesthetized and perfusion fixed for Hsp70 immunohistochemistry. After spinal ischemia or NMDA administration a neuronal Hsp70 expression was seen at 24h. After spinal hyperthermia only glial expression was seen at 4h. Hyperthermia significantly increased CSF glutamate concentration, however, MK-801 (a non-competitive NMDA receptor antagonist) pretreatment failed to block Hsp70 expression. After hypothermia or potassium depolarization only minimal or no Hsp70 expression was seen in glial cells. Exposure of neuronal tissue to a specific stimuli may lead to intervals of increased resistance to subsequent neurotoxic/ischemic insult. The intervening biochemistry of this protection has been attributed to a family of molecules referred to as HSP. In the present study, we demonstrate that short-lasting anoxic depolarization or activation of NMDA receptor are the most potent stimuli for spinal neuronal Hsp70 induction. This effect corresponds with the observed ischemic tolerance state induced by short-lasting preconditioning spinal ischemia.
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PMID:Spinal heat shock protein (70) expression: effect of spinal ischemia, hyperthermia (42 degrees C)/hypothermia (27 degrees C), NMDA receptor activation and potassium evoked depolarization on the induction. 1296 88

Heme oxygenase-1 (HO-1) is a member of the heat shock protein family (HSP-32). It responds to thermal stress in cultured glial cells. To our knowledge. nothing is known about the expression and response of the HO-1 in cerebral ischemia. Therefore, we show here the induction of HO-1 in the brain of mice after global cerebral ischemia. HO-1-like immunoreactivity was detected at 12, 24, and 48 hours after ischemia recirculation. The HO-1-like immunoreactive cells were observed in astrocytes in the hippocampal dentate gyrus and CA1. The peak level of HO-1-like immunoreactivity was found 48 hours after the recirculation. HO-1-like immunoreactivity was observed in GFAP-positive astrocytes by use of a double immunostaining method. These results provide direct evidence for the induction and localization of HO-1 immunoreactivity in vivo in a mouse cerebral ischemia. We suggest that HO-1, produced in astrocytes after ischemia-recirculation, may directly affect neurons to protect from cell death.
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PMID:Hippocampal heme oxigenase-1 in a murine cardiac arrest model. 1475 15

Growing evidence from in vitro studies supports that valproic acid (VPA), an anti-convulsant and mood-stabilizing drug, has neuroprotective effects. The present study investigated whether VPA reduces brain damage and improves functional outcome in a transient focal cerebral ischemia model of rats. Subcutaneous injection of VPA (300 mg/kg) immediately after ischemia followed by repeated injections every 12 h, was found to markedly decrease infarct size and reduce ischemia-induced neurological deficit scores measured at 24 and 48 h after ischemic onset. VPA treatment also suppressed ischemia-induced neuronal caspase-3 activation in the cerebral cortex. VPA treatments resulted in a time-dependent increase in acetylated histone H3 levels in the cortex and striatum of both ipsilateral and contralateral brain hemispheres of middle cerebral artery occlusion (MCAO) rats, as well as in these brain areas of normal, non-surgical rats, supporting the in vitro finding that VPA is a histone deacetylase (HDAC) inhibitor. Similarly, heat shock protein 70 (HSP70) levels were time-dependently up-regulated by VPA in the cortex and striatum of both ipsilateral and contralateral sides of MCAO rats and in these brain areas of normal rats. Altogether, our results demonstrate that VPA is neuroprotective in the cerebral ischemia model and suggest that the protection mechanisms may involve HDAC inhibition and HSP induction.
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PMID:Valproic acid reduces brain damage induced by transient focal cerebral ischemia in rats: potential roles of histone deacetylase inhibition and heat shock protein induction. 1518 38

HSP 70 is an important protein that repairs damaged tissue after injury. In the present study, we investigated the expression of HSP 70 and its mRNAs during ischemia-reperfusion in the rat bladder. Rat abdominal aorta was clamped with a small clip to induce ischemia-reperfusion injury in the bladder dome. Male Wistar rats, 8 weeks old, were divided into six groups: controls, 30-min ischemia, 30-min ischemia and 30-, 60-minute, 1- and 7-day reperfusion, groups A, B, C, D, E, and F, respectively. In functional studies, contractile responses to carbachol were measured in these groups. The expression of HSP 70-1/2 mRNAs was quantified using a real-time PCR method, and that of HSP 70 proteins was measured using ELISA in the bladders. In the functional study, Emax values of carbachol to bladders in the A, B, C, D, E and F groups were 9.3 +/- 1.3, 7.9 +/- 1.7, 4.3 +/- 0.8, 4.2 +/- 0.7, 4.5 +/- 0.6, and 8.1 +/- 1.2 g/mm2, respectively. In the control group, the expression of HSP 70-1/2 mRNA was detected, and the expression of HSP 70-1 mRNAs was significantly higher than that of HSP 70-2 mRNAs in each group. The expression of HSP 70-1 mRNA increased in groups B and C, but decreased in groups D, E, and F. The expression of HSP 70-2 mRNA in group C was significantly higher than that of groups A, D, E, and F. The expression of HSP 70-1/2 mRNAs after 1 day or 1 week of reperfusion was similar to control levels. The expression of HSP 70 proteins was increased shortly after the expression of their mRNAs. The expression of HSP 70 after 1 day or 1 week of reperfusion was almost identical to control levels. Our data indicate that contractile responses of the bladder were decreased by ischemia reperfusion, and that expression of HSP 70 and its mRNAs appeared to increase after a short period of the insult.
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PMID:Expression of HSP 70 and its mRNAS during ischemia-reperfusion in the rat bladder. 1530 31

Nitric oxide and other reactive nitrogen species appear to play crucial roles in the brain such as neuromodulation, neurotransmission and synaptic plasticity, but are also involved in pathological processes such as neurodegeneration and neuroinflammation. Acute and chronic inflammation result in increased nitrogen monoxide formation and nitrosative stress. It is now well documented that NO and its toxic metabolite, peroxynitrite, can inhibit components of the mitochondrial respiratory chain leading to cellular energy deficiency and, eventually, to cell death. Within the brain, the susceptibility of different brain cell types to NO and peroxynitrite exposure may be dependent on factors such as the intracellular reduced glutathione and cellular stress resistance signal pathways. Thus neurons, in contrast to astrocytes, appear particularly vulnerable to the effect of nitrosative stress. Evidence is now available to support this scenario for neurological disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, multiple sclerosis and Huntington's disease, but also in the brain damage following ischemia and reperfusion, Down's syndrome and mitochondrial encephalopathies. To survive different types of injuries, brain cells have evolved integrated responses, the so-called longevity assurance processes, composed of several genes termed vitagenes and including, among others, members of the HSP system, such as HSP70 and HSP32, to detect and control diverse forms of stress. In particular, HSP32, also known as heme oxygenase-1 (HO-1), has received considerable attention, as it has been recently demonstrated that HO-1 induction, by generating the vasoactive molecule carbon monoxide and the potent antioxidant bilirubin, could represent a protective system potentially active against brain oxidative injury. Increasing evidence suggests that the HO-1 gene is redox-regulated and its expression appears closely related to conditions of oxidative and nitrosative stress. An amount of experimental evidence indicates that increased rate of free radical generation and decreased efficiency of the reparative/degradative mechanisms, such as proteolysis, are factors that primarily contribute to age-related elevation in the level of oxidative stress and brain damage. Given the broad cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological agents capable of inducing such a response. These findings have led to new perspectives in medicine and pharmacology, as molecules inducing this defense mechanism appear to be possible candidates for novel, cytoprotective strategies. Particularly, manipulation of endogenous cellular defense mechanisms such as the heat shock response, through nutritional antioxidants or pharmacological compounds, represents an innovative approach to therapeutic intervention in diseases causing tissue damage, such as neurodegeneration. Consistent with this notion, maintenance or recovery of the activity of vitagenes may possibly delay the aging process and decrease the occurrence of age-related diseases with resulting prolongation of a healthy life span.
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PMID:Nitric oxide and cellular stress response in brain aging and neurodegenerative disorders: the role of vitagenes. 1534 Nov 81

Review of results of experimental and clinical studies indicates that the penumbra of physiologically impaired but potentially salvageable tissue surrounding the central core of focal cerebral ischemia that develops shortly after onset of major conducting vessel occlusion is complex and dynamic with severity and duration thresholds for hypoxic stress and injury that are specific to tissue site, cell type, molecular pathway or gene expression investigated and efficiency of collateral or residual flow and reperfusion. Imaging methods that have been utilized in vivo to identify penumbra and predict response to reperfusion and other protective therapies include magnetic resonance spectroscopy, diffusion- and perfusion-MRI as well as positron emission tomography. However, resolution of focal lesions characterized by lactic acidosis or cellular edema does not predict tissue survival, and imaging thresholds for resuscitation after reperfusion have not been determined experimentally. HSP-70 stress protein induction represents an endogenous protective mechanism that occurs in penumbra but not core neurones. A robust protective effect has been demonstrated during focal ischemia in transgenic mice overexpressing HSP-70 perhaps by suppressing early cytochrome c release. Delayed manganese mediated striatal neurodegeneration can be detected with T1 MRI after brief episodes of transient focal ischemia. Future studies may define endogenous cytotoxic and cytoprotective molecular penumbras that can be exploited to improve outcome after temporary focal ischemia.
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PMID:Molecular identification of the ischemic penumbra. 1548 32

Inducible head shock protein 70 kD (HSP-70i) has been shown to protect cells, tissues, and organs from harmful assaults in vivo and in vitro experimental models. Hemorrhagic shock followed by resuscitation is the principal cause of death among trauma patients and soldiers in the battlefield. Although the underlying mechanisms are still not fully understood, it has been shown that nitric oxide (NO) overproduction and inducible nitric oxide synthase (iNOS) overexpression play important roles in producing injury caused by hemorrhagic shock including increases in polymorphonuclear neutrophils (PMN) infiltration to injured tissues and leukotriene B(4) (LTB(4)) generation. Moreover, transcription factors responsible for iNOS expression are also altered by hemorrhage and resuscitation. It has been evident that either up-regulation of HSP-70i or down-regulation of iNOS can limit tissue injury caused by ischemia/reperfusion or hemorrhage/resuscitation. In our laboratory, geldanamycin, a member of ansamycin family, has been shown to induce HSP- 70i overexpression and then subsequently to inhibit iNOS expression, to reduce cellular caspase-3 activity, and to preserve cellular ATP levels. HSP-70i is found to couple to iNOS and its transcription factor. Therefore, the complex formation between HSP-70i and iNOS may be a novel mechanism for protection from hemorrhage/resuscitation-induced injury.
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PMID:Inducible heat shock protein 70 kD and inducible nitric oxide synthase in hemorrhage/resuscitation-induced injury. 1562 11

Previous studies have strongly suggested that heat shock protein 70 (HSP70) has protective effects in ischemia/reperfusion in tissues such as brain, heart, and liver. This study was performed to assess the efficacy of the HSP70 inducer geranylgeranylacetone (GGA) in experiments involving permanent middle cerebral artery (MCA) occlusion. Male Balb/c mice were subjected to permanent MCA occlusion by direct occlusion through small craniectomy. Vehicle or GGA (200 or 1000 mg/kg) was injected intraperitoneally 1 h prior to the onset of ischemia. Infarct volumes were evaluated at 24 h of ischemia by using 2,3,5-triphenyltetrazolium chloride (TTC) staining. The effect of GGA on the induction of HSP70 was studied at 3 h after ischemia with fluorescence immunocytochemistry. The percentage of infarct volume in the control mice (n=10) was 23.0+/-4.0% (mean+/-SD) of the contralateral hemisphere, while those in the treated groups were 22.6+/-7.3% (200 mg/kg group; n=5, P>0.05) and 15.7+/-3.8% (1000 mg/kg group; n=5, P<0.05). Pretreatments with 1000 mg/kg of GGA enhanced the ischemia-related induction of HSP in the neurons and astrocytes in the boundary zone of infarct. The results demonstrate that GGA significantly reduces infarct volume due to permanent MCA occlusion when given 1 h prior to the induction of ischemia.
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PMID:Neuroprotective effect of a heat shock protein inducer, geranylgeranylacetone in permanent focal cerebral ischemia. 1568 Sep 57


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