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)

Cold ischemia-warm reperfusion injury of liver grafts has been investigated thoroughly, but its underlying mechanism remains poorly understood. Here we show that autophagy is involved not only during cold preservation but also during warm reperfusion following transplantation. Immunohistochemistry using an antibody against LC3, a microtubule associated protein 1 light chain 3 and a marker of autophagosomes, showed dot-like weak staining in hepatocytes of rat liver grafts during cold preservation. Since University of Wisconsin solution for graft preservation lacks amino acids, the induction of autophagy in hepatocytes was similar to that under starvation conditions. Intense immunopositive punctate structures were detected abundantly in the hepatocytes 30 min after the beginning of reperfusion. LC3-positive granules were often co-localized in ED2-positive Kupffer cells at 60 min of the reperfusion phase. The molecular form of LC3 was mainly LC3-II, a membrane-bound form, during reperfusion, especially at 30 min of the phase. Electron microscopic examination demonstrated numerous vacuolar structures in hepatocytes at 30 min of the reperfusion period, while some hepatocytes with such vacuolar structures were present in the sinusoidal lumen. At the late stage of the reperfusion period, Kupffer cells contained phagocytosed cells that possessed numerous autophagic vacuoles/autolysosomes and nuclei with condensed chromatin. Our results showing the presence of autophagic vacuoles/autolysosomes in hepatocytes of liver grafts after the start of reperfusion suggest that warm reperfusion acted as a stress stimulus to hepatocytes. Moreover, the stress response of hepatocytes may be involved in their degeneration process.
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PMID:Participation of autophagy in the degeneration process of rat hepatocytes after transplantation following prolonged cold preservation. 1582 80

Hypoxia/ischemia (H/I) brain injury at birth is an important cause of cerebral palsy, mental retardation, and epilepsy. The H/I insult also causes energy failure, oxidative stress, and unbalanced ion fluxes, leading to high induction of autopahgy in brain neurons. Since the mice unable to execute autophagy (due to brain-specific deletion of Atg7 or Atg5) die by massive loss of cerebral and cerebellar neurons with accumulation of ubiquitin aggregates, induction of neuronal autophagy after H/I injury is generally considered neuroprotective by maintaining cellular homeostasis. However, our recent results show that hippocampal pyramidal neurons undergoing caspase-dependent or -independent death following neonatal H/I injury possess abundant LC3-positive granules, and such H/I neuronal death is largely prevented by Atg7 deficiency. In the present review we discuss the roles of autophagy and other forms of programmed cell death in the neonatal H/I brain insult.
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PMID:Autophagic neuron death in neonatal brain ischemia/hypoxia. 1821 31

Autophagy is a homeostatic cellular process required for the recycling of proteins and damaged organelles, and in most scenarios is believed to promote cell survival. However, there is accumulating evidence that under certain pathological situations, autophagy can also trigger and mediate programmed cell death (type II death). Despite the well-established pathophysiological role of apoptosis (type I cell death) in post-ischemic neuron death, there is now increasing interest whether alternative types of programmed cell death might be involved in regulation of neuronal death after both global and focal cerebral ischemia. Initial studies demonstrating the involvement of lysosomal proteases of the cathepsin family in neuron death after global ischemia already had suggested that this type of cell death may occur in an autophagy-dependent manner. Recently it was also shown that focal ischemia is associated with potently enhanced expression of the autophagy regulator Beclin 1 and subcellular redistribution of the autophagic marker LC3 to vacuolic structures in ischemic neurons. Increasing evidence suggests that the effects of autophagy are highly contextual. An insufficient autophagic response might render cells more susceptible to stress conditions whereas on the other hand prolonged overactivation of autophagy can lead to a complete self digestion of the cell. The extent of autophagy may represent a master switch between cell survival and cell death, and it will be of fundamental importance to dissect whether autophagy is primarily a strategy for survival or whether autophagy can also be a part of a cell death program and thus contribute to cell death after cerebral ischemia. A profound understanding of the biological effects and the mechanisms underlying ischemia-induced autophagy in neurons might be helpful in seeking effective new treatments for cerebral ischemia.
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PMID:Apoptosis meets autophagy-like cell death in the ischemic penumbra: Two sides of the same coin? 1831 39

It has been reported that ischemic insult increases the formation of autophagosomes and activates autophagy. However, the role of autophagy in ischemic neuronal damage remains elusive. This study was taken to assess the role of autophagy in ischemic brain damage. Focal cerebral ischemia was introduced by permanent middle cerebral artery occlusion (pMCAO). Activation of autophagy was assessed by morphological and biochemical examinations. To determine the contribution of autophagy/lysosome to ischemic neuronal death, rats were pretreated with a single intracerebral ventricle injection of the autophagy inhibitors 3-methyl-adenine (3-MA) and bafliomycin A1 (BFA) or the cathepsin B inhibitor Z-FA-fmk after pMCAO. The effects of 3-MA and Z-FA-fmk on brain damage, expression of proteins involved in regulation of autophagy and apoptosis were assessed with 2,3,5-triphenyltetrazolium chloride (TTC) staining and immunoblotting. The results showed that pMACO increased the formation of autophagosomes and autolysosomes, the mRNA and protein levels of LC3-II and the protein levels of cathepsin B. 3-MA, BFA and Z-FA-fmk significantly reduced infarct volume, brain edema and motor deficits. The neuroprotective effects of 3-MA and Z-FA-fmk were associated with an inhibition on ischemia-induced upregulation of LC3-II and cathepsin B and a partial reversion of ischemia-induced downregulation of cytoprotective Bcl-2. These results demonstrate that ischemic insult activates autophagy and an autophagic mechanism may contribute to ischemic neuronal injury. Thus, autophagy may be a potential target for developing a novel therapy for stroke.
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PMID:Neuronal injury in rat model of permanent focal cerebral ischemia is associated with activation of autophagic and lysosomal pathways. 1856 42

The Bcl-2 associated athanogene (BAG) family of proteins function as cochaperones by bridging molecules that recruit molecular chaperones to target proteins. BAG-1 provides a physical link between the heat shock proteins Hsc70/Hsp70 and the proteasome to facilitate ubiquitin-proteasome-mediated protein degradation. In addition to the proteasome, protein degradation via autophagy is responsible for maintaining cellular metabolism, organelle homeostasis and redox equilibrium. Our recent report shows that autophagy plays an important role in cardiac adaptation-induced cell survival against ischemia-reperfusion injury in association with the BAG-1 protein. BAG-1 is associated with the autophagosomal membrane protein LC3-II and it may participate in the induction of autophagy via Hsc70. Moreover, another BAG family member, BAG-3, is responsible for the induction of macroautophagy in association with HspB8. These results show the involvement of BAG family members in the induction of autophagy for the degradation of damaged or oxidized proteins to promote cell survival.
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PMID:BAG-1 induces autophagy for cardiac cell survival. 1900 66

Autophagy, a highly conserved cellular mechanism wherein various cellular components are broken down and recycled through lysosomes, occurs constitutively in the heart and may serve as a cardioprotective mechanism in some situations. It has been implicated in the development of heart failure and is up-regulated following ischemia-reperfusion injury. Autophagic flux, a measure of autophagic vesicle formation and clearance, is an important measurement in evaluating the efficacy of the pathway, however, tools to measure flux in vivo have been limited. Here, we describe the use of monodansylcadaverine (MDC) and the lysosomotropic drug chloroquine to measure autophagic flux in in vivo model systems, specifically focusing on its use in the myocardium. This method allows determination of flux as a more precise measure of autophagic activity in vivo much in the same way that Bafilomycin A(1) is used to measure flux in cell culture. MDC injected 1 h before sacrifice, colocalizes with mCherry-LC3 puncta, validating its use as a marker of autophagosomes. This chapter provides a method to measure autophagic flux in vivo in both transgenic and nontransgenic animals, using MDC and chloroquine, and in addition describes the mCherry-LC3 mouse and the advantages of this animal model in the study of cardiac autophagy. Additionally, we review several methods for inducing autophagy in the myocardium under pathological conditions such as myocardial infarction, ischemia/ reperfusion, pressure overloading, and nutrient starvation.
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PMID:Novel methods for measuring cardiac autophagy in vivo. 1921 14

Ischemia/reperfusion (I/R) injury, which induces extensive loss of tubular epithelial cells, is associated with delayed graft function following kidney transplantation. Recent reports have suggested that cell death by I/R injury occurs by autophagy, a cellular degradation process responsible for the turnover of unnecessary or dysfunctional organelles and cytoplasmic proteins, as well as by apoptosis. Recently, we demonstrated that overexpression of the anti-apoptotic factor, Bcl-2, inhibited tubular apoptosis and subsequent tubulointerstitial damage after I/R injury. Autophagy is also observed in cells undergoing cell death in several diseases. Therefore, we hypothesized that increased Bcl-2 protein may protect tubular epithelial cells by suppressing autophagy and inhibiting apoptosis. In the present study, a transgenic mouse model (LC3-GFP TG) in which autophagosomes are labeled with LC3-GFP and Bcl-2/LC3-GFP double transgenic mice (Bcl-2/LC3-GFP TG) were used to examine the effect of Bcl-2 on I/R-induced autophagy. I/R injury, which is associated with marked disruption of normal tubular morphology, promoted the formation of LC3-GFP dots, representing extensively induced autophagosomes. On electron microscopy, the autophagosomes contained mitochondria in I/R-injured tubular epithelial cells. In contrast, Bcl-2 augmentation suppressed the formation of autophagosomes and there was less tubular damage. In conclusion, Bcl-2 augmentation protected renal tubular epithelial cells from I/R injury by suppressing autophagosomal degradation and inhibiting tubular apoptosis.
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PMID:Bcl-2 protects tubular epithelial cells from ischemia/reperfusion injury by dual mechanisms. 1924 73

In the heart, autophagy is required for normal cardiac function and also has been implicated in cardiovascular disease. FoxO transcription factors promote autophagy in skeletal muscle and have additional roles in regulation of cell size, proliferation, and metabolism. Here we investigate the role of FoxO transcription factors in regulating autophagy and cell size in cardiomyocytes. In cultured rat neonatal cardiomyocytes, glucose deprivation leads to decreased cell size and induction of autophagy pathway genes LC3, Gabarapl1, and Atg12. Likewise, overexpression of either FoxO1 or FoxO3 reduces cardiomyocyte cell size and induces expression of autophagy pathway genes. Moreover, inhibition of FoxO activity by dominant negative FoxO1 (Delta256) blocks cardiomyocyte cell size reduction upon starvation, suggesting the necessity of FoxO function in cardiomyocyte cell size regulation. Under starvation conditions, endogenous FoxO1 and FoxO3 are localized to the nucleus and bind to promoter sequences of Gabarapl1 and Atg12. In vivo studies show that cellular stress, such as starvation or ischemia/reperfusion in mice, results in induction of autophagy in the heart with concomitant dephosphorylation of FoxO, consistent with increased activity of nuclear FoxO transcription factors. Together these results provide evidence for an important role for FoxO1 and FoxO3 in regulating autophagy and cell size in cardiomyocytes.
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PMID:FoxO transcription factors promote autophagy in cardiomyocytes. 1969 26

Reactive oxygen species (ROS) are involved in several cell death processes, including cerebral ischemic injury. We found that glutamate-induced ROS accumulation and the associated cell death in mouse hippocampal cell lines were delayed by pharmacological inhibition of autophagy or lysosomal activity. Glutamate, however, did not stimulate autophagy, which was assessed by a protein marker, LC3, and neither changes in organization of mitochondria nor lysosomal membrane permeabilization were observed. Fluorescent analyses by a redox probe PF-H(2)TMRos revealed that autophagosomes and/or lysosomes are the major sites for basal ROS generation in addition to mitochondria. Treatments with inhibitors for autophagy and lysosomes decreased their basal ROS production and caused a burst of mitochondrial ROS to be delayed. On the other hand, attenuation of mitochondrial activity by serum depletion or by high cell density culture resulted in the loss of both constitutive ROS production and an ROS burst in mitochondria. Thus, constitutive ROS production within mitochondria and lysosomes enables cells to be susceptible to glutamate-induced oxidative cytotoxicity. Likewise, inhibitors for autophagy and lysosomes reduced neural cell death in an ischemia model in rats. We suggest that cell injury during periods of ischemia is regulated by ROS-generating activity in autophagosomes and/or lysosomes as well as in mitochondria.
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PMID:Constitutive reactive oxygen species generation from autophagosome/lysosome in neuronal oxidative toxicity. 1985 Sep 31

Previously, we showed that sulfaphenazole (SUL), an antimicrobial agent that is a potent inhibitor of cytochrome P4502C9, is protective against ischemia-reperfusion (I/R) injury (Ref. 15). The mechanism, however, underlying this cardioprotection, is largely unknown. With evidence that activation of autophagy is protective against simulated I/R in HL-1 cells, and evidence that autophagy is upregulated in preconditioned hearts, we hypothesized that SUL-mediated cardioprotection might resemble ischemic preconditioning with respect to activation of protein kinase C and autophagy. We used the Langendorff model of global ischemia to assess the role of autophagy and protein kinase C in myocardial protection by SUL during I/R. We show that SUL enhanced recovery of function, reduced creatine kinase release, decreased infarct size, and induced autophagy. SUL also triggered PKC translocation, whereas inhibition of PKC with chelerythrine blocked the activation of autophagy in adult rat cardiomyocytes. In the Langendorff model, chelerythrine suppressed autophagy and abolished the protection mediated by SUL. SUL increased autophagy in adult rat cardiomyocytes infected with GFP-LC3 adenovirus, in isolated perfused rat hearts, and in mCherry-LC3 transgenic mice. To establish the role of autophagy in cardioprotection, we used the cell-permeable dominant-negative inhibitor of autophagy, Tat-Atg5(K130R). Autophagy and cardioprotection were abolished in rat hearts perfused with recombinant Tat-Atg5(K130R). Taken together, these studies indicate that cardioprotection mediated by SUL involves a PKC-dependent induction of autophagy. The findings suggest that autophagy may be a fundamental process that enhances the heart's tolerance to ischemia.
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PMID:Autophagy and protein kinase C are required for cardioprotection by sulfaphenazole. 2000 75


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