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)

Ischemic preconditioning (PC) suppresses chemical coupling of cardiomyocytes via gap junctions (GJs) during ischemia, which is an adjunct mechanism of protection. The aim of this study was to characterize roles of protein kinases in PC-induced GJ modulation. In isolated rat hearts, ventricular tissues were sampled before and after ischemia with or without PC, and intercalated disc-rich fractions were separated for immunoprecipitation and immunoblotting. Levels of protein kinase C (PKC)-epsilon, p38mitogen-activated protein kinase (MAPK)-alpha, and Src coimmunoprecipitated with connexin-43 (Cx43) were increased after ischemia, whereas p38MAPKbeta was not detected in the Cx43 immunoprecipitates. PC did not modify the level of Cx43-Src complex after ischemia. However, PC enhanced Cx43-PKCepsilon complex formation, which was abolished by PKCepsilon translocation inhibitory peptide (TIP). In contrast, PC reduced Cx43-p38MAPKalpha complex level and p38MAPK activity in the Cx43 immunoprecipitates after ischemia. The effect of PC on Cx43-p38MAPKalpha interaction was mimicked by SB-203580, a p38MAPK inhibitor. PC reduced permeability of GJs to Lucifer yellow in the myocardium at 25 min after ischemia, and this effect was abolished by PKCepsilon-TIP. SB-203580 increased the GJ permeability at 15 min after ischemia compared with that in untreated controls, but the difference became insignificant 25 min after ischemia. In conclusion, PC has distinct effects on interaction of GJ Cx43 with PKCepsilon, p38MAPKalpha, and Src during ischemia. Suppression of GJ permeability during ischemia by PC is primarily achieved by enhanced interaction of Cx43 with PKCepsilon, which overwhelms the counterbalancing effect of reduced Cx43-p38MAPKalpha interaction.
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PMID:Roles of Cx43-associated protein kinases in suppression of gap junction-mediated chemical coupling by ischemic preconditioning. 1909 15

Hemichannels are transmembrane channels that represent the functional subunits of gap junctions. Each hemichannel is composed of a connexin or pannexin hexamer and, after being transported to the membrane, remains unpaired until it is incorporated in a gap junction. Several studies have already provided evidence that gap junction-mediated intercellular diffusion of ions and small molecules during ischemia represents an important mechanism through which necrotic, apoptotic, or even protective signals are transported between cells. Although initially hemichannels were supposed to be functional only in gap junctions, recent findings indicate that unpaired hemichannels also display a large array of activities that can be modulated under several pathophysiological conditions, including ischemia. Open hemichannels in ischemia dramatically alter the permeability properties of membranes and lead to cell death through ionic dysregulation, loss of metabolites, and changes in intracellular ATP. This review focuses on the properties and possible functions of unpaired connexin and pannexin hemichannels and the implications this has for a variety of events, such as cell death, glutamate release, oxidative stress, cortical spreading depression, that occur during an ischemic insult and may affect its outcome.
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PMID:Hemichannels in cerebral ischemia. 1927 26

Postconditioning (PostC) may limit mitochondrial damage and apoptotic signaling. We studied markers of apoptosis and mitochondrial protection in isolated rat hearts, which underwent a) perfusion without ischemia (Sham), b) 30-min ischemia (I) plus 2-hour reperfusion (R), or c) PostC protocol (5 intermittent cycles of 10-s reperfusion and 10-s ischemia immediately after the 30-min ischemia). Markers were studied in cytosolic (CF) and/or mitochondrial (MF) fractions. In CF, while pro-apoptotic factors (cytochrome c and caspase-3) were reduced, the anti-apoptotic markers (Bcl-2 and Pim-1) were increased by PostC, compared to the I/R group. Accordingly, phospho-GSK-3beta and Bcl-2 levels increased in mitochondria of PostC group. Moreover, I/R reduced the level of mitochondrial structural protein (HSP-60) in MF and increased in CF, thus suggesting mitochondrial damage and HSP-60 release in cytosol, which were prevented by PostC. Electron microscopy confirmed that I/R markedly damaged cristae and mitochondrial membranes; damage was markedly reduced by PostC. Finally, total connexin-43 (Cx43) levels were reduced in the CF of the I/R group, whereas phospho-Cx43 level resulted in higher levels in the MF of the I/R group than the Sham group. PostC limited the I/R-induced increase of mitochondrial phospho-Cx43. Data suggest that PostC i) increases the levels of anti-apoptotic markers, including the cardioprotective kinase Pim-1, ii) decreases the pro-apoptotic markers, e.g. cytochrome c, iii) preserves the mitochondrial structure, and iv) limits the migration of phospho-Cx43 to mitochondria.
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PMID:Postconditioning induces an anti-apoptotic effect and preserves mitochondrial integrity in isolated rat hearts. 2970 30

Connexin 43 (Cx43) is the most prominent connexin in the mammalian ventricular myocardium and forms gap junctions that are essential for normal conduction of action potential. Carvedilol, a nonselective beta-blocker, is widely used to prevent ventricular arrhythmias after myocardial infarction (MI). Here, we examined the effect of carvedilol on the expression of Cx43 protein and ventricular fibrillation threshold (VFT) using a rat MI model. VFT is defined as the lowest voltage, at which ventricular fibrillation is induced by electrical stimulation. Adult male Wister rats were divided into sham-operated group (n = 20) and MI groups treated with intragastric administration of saline (control, n = 30) or carvedilol (2.5 mg/kg, n = 30) twice a day for 7 days immediately after ligation of the left coronary artery. Compared with sham group (100%), total Cx43 protein and phosphorylated Cx43 protein were decreased in the MI rats to 60 +/- 21% and 52 +/- 19% (both P < 0.05), respectively. Treatment with carvedilol prevented the MI-induced decrease in total and phosphorylated Cx43 levels (91 +/- 17% and 80 +/- 20%, both P < 0.05), respectively, which were similar to the levels of sham animals. Moreover, the MI rats exhibited a marked decrease in VFT compared with the sham group (7.2 +/- 1.30 vs. 13.0 +/- 2.12 V, P < 0.05), but the decrease was abolished by carvedilol (11.0 +/- 2.65 V). In conclusion, carvedilol might prevent the ischemia-induced ventricular arrhythmias by restoring Cx43 protein and VFT to the basal levels.
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PMID:Carvedilol ameliorates the decreases in connexin 43 and ventricular fibrillation threshold in rats with myocardial infarction. 1947 68

Numerous cell types express functional connexin (Cx) hemichannels (HCs), and membrane depolarization and/or exposure to a divalent cation-free bathing solution (DCFS) have been shown to promote HC opening. However, little is known about conditions that can promote HC opening in the absence of strong depolarization and when extracellular divalent cation concentrations remain at physiological levels. Here the effects of metabolic inhibition (MI), an in vitro model of ischemia, on the activity of mouse Cx32 HCs were examined. In HeLa cells stably transfected with mouse Cx32 (HeLa-Cx32), MI induced an increase in cellular permeability to ethidium (Etd). The increase in Etd uptake was directly related to an increase in levels of Cx32 HCs present at the cell surface. Moreover, MI increased membrane currents in HeLa-Cx32 cells. Underlying these currents were channels exhibiting a unitary conductance of approximately 90 pS, consistent with Cx32 HCs. These currents and Etd uptake were blocked by HC inhibitors. The increase in Cx32 HC activity was preceded by a rapid reduction in mitochondrial membrane potential and a rise in free intracellular Ca(2+) concentration ([Ca(2+)](i)). The increase in free [Ca(2+)](i) was prevented by HC blockade or exposure to extracellular DCFS and was virtually absent in parental HeLa cells. Moreover, inhibition of Cx32 HCs expressed by HeLa cells in low-confluence cultures drastically reduced cell death induced by oxygen-glucose deprivation, which is a more physiological model of ischemia-reperfusion. Thus HC blockade could reduce the increase in free [Ca(2+)](i) and cell death induced by ischemia-like conditions in cells expressing Cx32 HCs.
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PMID:Metabolic inhibition increases activity of connexin-32 hemichannels permeable to Ca2+ in transfected HeLa cells. 1958 18

Nestin+ cardiac myocyte-like cells were detected in the peri-infarct/infarct region of the ischemically damaged heart. The present study was undertaken to elucidate the phenotype and potential origin of nestin+ cardiac myocyte-like cells and identify stimuli implicated in their appearance. In the infarcted human and rat heart, nestin+ cardiac myocyte-like cells were morphologically and structurally immature, exhibited a desmin-immunoreactive striated phenotype, expressed the beta(1)-adrenergic receptor, and associated with an aberrant pattern of connexin-43 expression and/or organization. Nestin+ cardiac myocyte-like cells were detected 24 h postischemic injury and persisted in the infarcted rat heart for 9 mo. In the normal rat heart, cardiac progenitor transcriptional factors Nkx2.5/GATA4 were detected in a subpopulation of nestin+ neural stem cells. Following an ischemic insult, nestin+/Nkx2.5+ neural stem cells migrated to the peri-infarct/infarct region and appeared to be in a primordial state of differentiation to a nestin+ cardiac myocyte-like cell. The exposure of adult male rats to normobaric hypoxia (12% O2) for 10 days failed to promote the appearance of nestin+ cardiac myocyte-like cells. Following osmotic pump delivery of isoproterenol to normal adult rats, nestin+ cardiac myocyte-like cells were detected, albeit the response was modest and secondary to tissue loss. Thus ischemia-induced appearance of nestin+ cardiac myocyte-like cells apparently represents an adaptive response to heal the infarcted heart. Nkx2.5/GATA4 expression in a subpopulation of resident neural stem cells provides the appropriate phenotype for their potential differentiation to a nestin+ cardiac myocyte-like cell.
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PMID:The phenotype and potential origin of nestin+ cardiac myocyte-like cells following infarction. 1967 43

Although the function of astrocytic gap junctions under ischemia is still under debate, increased expression of connexin 43 (Cx43) has been observed in ischemic brain lesions, suggesting that astrocytic gap junctions could provide neuronal protection against ischemic insult. Moreover, different connexin subtypes may play different roles in pathological conditions. We used immunohistochemical analysis to investigate alterations in the expression of connexin subtypes in human stroke brains. Seven samples, sectioned after brain embolic stroke, were used for the analysis. Data, evaluated semiquantitatively by computer-assisted densitometry, was compared between the intact hemisphere and ischemic lesions. The results showed that the coexpression of Cx32 and Cx45 with neuronal markers was significantly increased in ischemic lesions. Cx43 expression was significantly increased in the colocalization with astrocytes and relatively increased in the colocalization with neuronal marker in ischemic lesions. Therefore, Cx32, Cx43, and Cx45 may respond differently to ischemic insult in terms of neuroprotection.
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PMID:Ischemia alters the expression of connexins in the aged human brain. 1979 23

Gap junctions are intercellular channels that allow the passage of ions, small molecules, and second messengers that are essential for the coordination of cellular function. They are formed by two hemichannels, each constituted by the oligomerization of six connexins (Cx). Among the 21 different human Cx isoforms, studies have suggested that in the heart, Cx40 and Cx43 can oligomerize to form heteromeric hemichannels. The mechanism of heteromeric channel regulation has not been clearly defined. Tissue ischemia leads to intracellular acidification and closure of Cx43 and Cx40 homomeric channels. However, coexpression of Cx40 and Cx43 in Xenopus oocytes enhances the pH sensitivity of the channel. This phenomenon requires the carboxyl-terminal (CT) part of both connexins. In this study we used different biophysical methods to determine the structure of the Cx40CT and characterize the Cx40CT/Cx43CT interaction. Our results revealed that the Cx40CT is an intrinsically disordered protein similar to the Cx43CT and that the Cx40CT and Cx43CT can interact. Additionally, we have identified an interaction between the Cx40CT and the cytoplasmic loop of Cx40 as well as between the Cx40CT and the cytoplasmic loop of Cx43 (and vice versa). Our studies support the "particle-receptor" model for pH gating of Cx40 and Cx43 gap junction channels and suggest that interactions between cytoplasmic regulatory domains (both homo- and hetero-connexin) could be important for the regulation of heteromeric channels.
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PMID:Characterization of the structure and intermolecular interactions between the connexin40 and connexin43 carboxyl-terminal and cytoplasmic loop domains. 1980 65

Targeting of numerous transmembrane proteins to the cell surface is thought to depend on their recognition by cargo receptors that interact with the adaptor machinery for anterograde traffic at the distal end of the Golgi complex. We report here on consortin, a novel integral membrane protein that is predicted to be intrinsically disordered, i.e. that contains large segments whose native state is unstructured. We identified consortin as a binding partner of connexins, the building blocks of gap junctions. Consortin is located at the trans-Golgi network (TGN), in tubulovesicular transport organelles, and at the plasma membrane. It directly interacts with the TGN clathrin adaptors GGA1 and GGA2, and disruption of this interaction by expression of a consortin mutant lacking the acidic cluster-dileucine (DXXLL) GGA interaction motif causes an intracellular accumulation of several connexins. RNA interference-mediated silencing of consortin expression in HeLa cells blocks the cell surface targeting of these connexins, which accumulate intracellularly, whereas partial depletion and redistribution of the consortin pool slows down the intracellular degradation of gap junction plaques. Altogether, our results show that, by studying connexin trafficking, we have identified the first TGN cargo receptor for the targeting of transmembrane proteins to the plasma membrane. The identification of consortin provides in addition a potential target for therapies aimed at diseases in which connexin traffic is altered, including cardiac ischemia, peripheral neuropathies, cataracts and hearing impairment. Sequence accession numbers. GenBank: Human CNST cDNA, NM_152609; mouse Cnst cDNA, NM_146105.
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PMID:Consortin, a trans-Golgi network cargo receptor for the plasma membrane targeting and recycling of connexins. 1986 90

Gap junctions form electrical conduits between adjacent myocardial cells, permitting rapid spatial passage of the excitation current essential to each heartbeat. Arrhythmogenic decreases in gap junction coupling are a characteristic of stressed, failing, and aging myocardium, but the mechanisms of decreased coupling are poorly understood. We previously found that microtubules bearing gap junction hemichannels (connexons) can deliver their cargo directly to adherens junctions. The specificity of this delivery requires the microtubule plus-end tracking protein EB1. We performed this study to investigate the hypothesis that the oxidative stress that accompanies acute and chronic ischemic disease perturbs connexon forward trafficking. We found that EB1 was displaced in ischemic human hearts, stressed mouse hearts, and isolated cells subjected to oxidative stress. As a result, we observed limited microtubule interaction with adherens junctions at intercalated discs and reduced connexon delivery and gap junction coupling. A point mutation within the tubulin-binding domain of EB1 reproduced EB1 displacement and diminished connexon delivery, confirming that EB1 displacement can limit gap junction coupling. In zebrafish hearts, oxidative stress also reduced the membrane localization of connexin and slowed the spatial spread of excitation. We anticipate that protecting the microtubule-based forward delivery apparatus of connexons could improve cell-cell coupling and reduce ischemia-related cardiac arrhythmias.
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PMID:Limited forward trafficking of connexin 43 reduces cell-cell coupling in stressed human and mouse myocardium. 2003 8


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