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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study was aimed at characterizing alterations of the nucleotide content and morphological state of rat corticoencephalic cell cultures subjected to metabolic damage and treatment with modulators of mitochondrial ATP-dependent potassium channels (mitoK(ATP)). In a first series of experiments, in vitro ischemic changes of the contents of purine and pyrimidine nucleoside diphosphates and triphosphates were measured by high performance liquid chromatography (HPLC) and the corresponding histological alterations were determined by celestine blue/acid fuchsin staining. As an ischemic stimulus, incubation with a glucose-free medium saturated with argon was used. Ischemia decreased the levels of adenosine, guanine and uridine triphosphate (ATP, GTP, UTP) and increased the levels of the respective dinucleotides ADP and UDP, whereas the GDP content was not changed. Both 5-hydroxydecanoate (5-HD) and diazoxide failed to alter the contents of nucleoside diphosphates and triphosphates, when applied under normoxic conditions. 5-HD (30 microM) prevented the ischemia-induced changes of nucleotide and nucleoside levels. Diazoxide (300 microM), either alone or in combination with 5-hydroxydecanoate (30 microM) was ineffective. Pyruvate (5 mM) partially reversed the effects of ischemia or ischemia plus 2-deoxyglucose (20mM) in the incubation medium. Diazoxide (300 microM) and 5-HD (30 microM) had no effect in the presence of pyruvate (5mM) and 2-deoxyglucose (20mM). Staining the cells with celestine blue/acid fuchsin in order to classify them as intact, reversibly or profoundly injured, revealed a protective effect of 5-HD. When compared with 5-HD, diazoxide, pyruvate and 2-deoxyglucose had similar but less pronounced effects. In conclusion, these results suggest a protective role of 5-hydroxydecanoate on early corticoencephalic nucleotide and cell viability alterations during ischemia.
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PMID:Early biochemical and histological alterations in rat corticoencephalic cell cultures following metabolic damage and treatment with modulators of mitochondrial ATP-sensitive potassium channels. 1282 Sep 85

Heat shock proteins (hsp), hsp60 and hsp10, are involved in the folding of imported mitochondrial proteins and the refolding of denatured proteins after stress. We examined whether hsp10 can reduce myocyte death by its mitochondrial function or by interacting with cytoplasmic signaling pathways. Overexpression of hsp10 by adenoviral infection decreased myocyte death induced by hydrogen peroxide, sodium cyanide, and simulated ischemia and reoxygenation (SI/RO). We generated an adenoviral vector coding for a temperature-sensitive mutant hsp10 protein (P34H), incapable of cooperatively refolding denatured malate dehydrogenase with hsp60. Overexpression of the hsp10 mutant potentiated SI/RO-induced myocyte death. Analysis of electron transport chain function revealed increased Complex I capacity with hsp10 overexpression, whereas hsp10(P34H) overexpression decreased Complex II capacity. Hsp10 overexpression preserved both Complex I and II function after SI/RO. Examination of the Ras GTP-ase signaling pathway indicated that inhibition of Ras was required for protection by hsp10. Constitutive activation of Ras abolished the effects afforded by hsp10 and hsp10(P34H). Hsp10 overexpression inactivated Raf, ERK, and p90Ribosomal kinase (p90RSK) before and after SI/RO. Our results suggest that complex mechanisms are involved in the protection by hsp10 against SI/RO-induced myocyte death. This mechanism may involve the hsp10 mobile loop and attenuation of the Ras GTP-ase signaling pathway.
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PMID:Myocyte protection by 10 kD heat shock protein (Hsp10) involves the mobile loop and attenuation of the Ras GTP-ase pathway. 1505 67

C-Jun N-terminal kinase (JNK) is part of the mitogen-activated protein kinase (MAPK) family of signaling pathways that are induced in response to extracellular stimuli. JNK is primarily a stress-response pathway and can be activated by proinflammatory cytokines and growth factors coupled to membrane receptors or through non-receptor pathways by stimuli such as heat shock, UV irradiation, protein synthesis inhibitors, and conditions that elevate the levels of reactive oxygen intermediates (ROI). The molecular initiators of MAPKs by non-receptor stimuli have not been described. Ischemia followed by reperfusion or hypoxia with reoxygenation represents a condition of high oxidative stress where JNK activation is associated with elevated ROI. We show here that the activation of JNK by this condition is initiated in the mitochondria and requires coupled electron transport, ROI generation, and calcium flux. These signals cause the selective, sequential activation of the calcium-dependent, proline-rich kinase Pyk2 and the small GTP binding factors Rac-1 and Cdc42. Interruption of these interactions with inactivated dominant negative mutant proteins, blocking calcium flux, or inhibiting electron transport through mitochondrial complexes II, III, or IV prevents JNK activation and results in a proapoptotic phenotype that is characteristic of JNK inhibition in this model of ischemia-reperfusion. The signaling pathway is unique for the reoxygenation stimulus and provides a framework for other non-receptor-mediated pathways of MAPK activation.
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PMID:Mitochondrial signals initiate the activation of c-Jun N-terminal kinase (JNK) by hypoxia-reoxygenation. 1522 66

ATP concentration is dramatically affected in ischemic injury. From previous studies on ATP mediated purine and pyrimidine salvage in CNS, we observed that when "post-mitochondrial" extracts of rat brain were incubated with ATP at 3.6 mM, a normoxic concentration, formation of IMP always preceded that of adenosine, a well known neuroactive nucleoside and a homeostatic cellular modulator. This observation prompted us to undertake a study aimed at assessing the precise pathways and kinetics of ATP breakdown, a process considered to be the major source of adenosine in rat brain. The results obtained using post-mitochondrial extracts strongly suggest that the breakdown of intracellular ATP at normoxic concentration follows almost exclusively the pathway ATP<=>ADP<=>AMP --> IMP --> inosine<=>hypoxanthine, with little, if any, intracellular adenosine production. At low ischemic concentration, intracellular ATP breakdown follows the pathway ATP<=>ADP<=>AMP --> adenosine --> inosine<=>hypoxanthine with little IMP formation. At the same time, extracellular ATP, whose concentration is known to be enhanced during ischemia, is actively broken down to adenosine through the pathway ATP --> ADP --> AMP --> adenosine, catalysed by the well characterized ecto-enzyme cascade system. Moreover, we show that during intracellular GTP catabolism, xanthosine, in addition to guanosine, is generated through the so called "ribose 1-phosphate recycling for nucleoside interconversion". These results considerably extend our knowledge on the long debated question of the extra or intracellular origin of adenosine in CNS, suggesting that at least in normoxic conditions, intracellular adenosine is of extracellular origin.
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PMID:Metabolic regulation of ATP breakdown and of adenosine production in rat brain extracts. 1531 67

Current evidence strongly suggests that coronary atherosclerosis is a common denominator in patients with stable effort angina pectoris. The concept of pathophysiology of coronary atherosclerosis is presented--angiographic and pathologic evidence now suggest presence of eccentric and irregular atherosclerotic lesions (sometimes associated with plaque rupture) and simultaneously present endothelial dysfunction increases sensitivity of vascular smooth muscles to physical and biochemical stimuli with propensity to spasm. Ischemia is due to an increased myocardial oxygen demand (increased heart rate or blood pressure) that cannot be met because of fixed coronary reserve. The organic nitrates are important drugs for the treatment of patients wit angina. The mechanism(s) of their action is presented--biotransformation and liberation of nitric oxide which stimulates guanylyl cyclase and conversion of GTP (by guanylyl cyclase) to cGMP, which causes vasodilatation but reduces platelet adhesion and aggregation too. Sublingual nitroglycerin and isosorbide dinitrate are effective in the treatment of acute episodes of angina. Long-acting nitrate preparations are effectiveness include intermittent transdermal nitroglycerin, standard formulation and sustained-release isosorbid dinitrate (but better isosorbid-5-mononitrate because of longer duration of action of action and no 1st pass hepatic metabolism) (nitrate-free interval should be of 8-10 hours duration). The place of the therapy with betablockers and calcium channel blockers in angina pectoris is presented as well and their combination with nitrates.
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PMID:[Anti-angina treatment in stable forms of angina pectoris with emphasis on nitrates]. 1564 Dec 33

The discovery that a myoglobin-like hemeprotein (called neuroglobin) is expressed in our brain raised considerable curiosity from the standpoints of biochemistry and pathophysiology alike. Neuroglobin is involved in neuroprotection from damage due to hypoxia or ischemia in vitro and in vivo; overexpression of neuroglobin ameliorates the recovery from stroke in experimental animals. The mechanism underlying this remarkable effect is still mysterious. Structural studies revealed that neuroglobin has a typical globin fold, and despite being hexacoordinated, it binds reversibly O2, CO, and NO, undergoing a substantial conformational change of the heme and of the protein. The possible mechanisms involved in neuroprotection are briefly reviewed. Neuroglobin is unlikely to be involved in O2 transport (like myoglobin), although it seems to act as a sensor of the O2/NO ratio in the cell, possibly regulating the GDP/GTP exchange rate forming a specific complex with the G(alpha beta gamma)-protein when oxidized but not when bound to a gaseous ligand. Thus it appears that neuroglobin is a stress-responsive sensor for signal transduction in the brain, mediated by a ligand-linked conformational change of the protein.
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PMID:A globin for the brain. 1707 95

All transglutaminases share the common enzymatic activity of transamidation, or the cross-linking of glutamine and lysine residues to form N epsilon (gamma-glutamyl) lysyl isopeptide bonds. The plasma proenzyme factor XIII is responsible for stabilizing the fibrin clot against physical and fibrinolytic disruption. Another member of the transglutaminase family, tissue transglutaminase or TG2 is abundantly expressed in cardiomyocytes, vascular cells and macrophages. The transglutaminases have a variety of functions independent of their transamidating activity. For example, TG2 binds and hydrolyzes GTP, thereby fostering signal transduction by several G protein coupled receptors. Accumulating evidence points to novel roles for factor XIII and TG2 in cardiovascular biology including: (a) modulating platelet activity, (b) regulating glucose control, (c) contributing to the development of hypertension, (d) influencing the progression of atherosclerosis, (e) regulating vascular permeability and angiogenesis (f) and contributing to myocardial signaling, contractile activity and ischemia/reperfusion injury. In this review, we summarize the cardiovascular biology of two members of the family of transglutaminases, Factor XIII and TG2.
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PMID:Roles of transglutaminases in cardiac and vascular diseases. 1712 61

c-Jun NH(2)-terminal kinase (JNK), a member of the MAPK family of protein kinases, is a stress-response kinase that is activated by proinflammatory cytokines and growth factors coupled to membrane receptors or through nonreceptor pathways by stimuli such as heat shock, UV irradiation, protein synthesis inhibitors, and conditions that elevate the levels of reactive oxygen intermediates (ROI). Ischemia followed by reperfusion or hypoxia with reoxygenation represents a condition of high oxidative stress where JNK activation is associated with elevated ROI. We recently demonstrated that the activation of JNK by this condition is initiated by ROI generated by mitochondrial electron transport and involves sequential activation of the proline-rich kinase 2 and the small GTP-binding factors Rac-1 and Cdc42. Here we present evidence that protein kinase C (PKC) and transforming growth factor-beta-activated kinase-1 (TAK-1) are also components of this pathway. Inhibition of PKC with the broad-range inhibitor calphostin C, the PKC-alpha/beta-selective inhibitor Go9367, or adenovirus-expressing dominant-negative PKC-alpha blocked the phosphorylation of proline-rich kinase 2 and JNK. Reoxygenation activated the mitogen-activated protein kinase kinase kinase, TAK-1, and promoted the formation of a complex containing Rac-1, TAK-1, and JNK but not apoptosis-stimulating kinase-1 or p21-activated kinase-1, which was detected within the first 10 min of reoxygenation. These results identify two new components, PKC and TAK-1, that have not been previously described in this signaling pathway.
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PMID:PKC-alpha and TAK-1 are intermediates in the activation of c-Jun NH2-terminal kinase by hypoxia-reoxygenation. 1720 6

Islets from brain-dead donors (BDDs) are being used in the treatment of Type 1 diabetes. However, both donor numbers and islet survival are limited. We explored the clinical potential for islets from non-heart-beating donors (NHBDs), who have lower circulating cytokines, by comparing islets from 10 NHBDs against 12 identically-isolated islets from BDDs over the same time period. The quantity and quality of islets from NHBDs was good. NHBD yielded approximately 12.6% more islets than those of BDDs (505,000 +/- 84,230 vs. 400,970 +/- 172,430 islet equivalent number [IEQ]/pancreas, p = 0.01) with comparable viability. ATP and GTP contents were lower (6.026 +/- 3.076 vs. 18.105 +/- 7.8 nM/mg protein, p = 0.01 and 1.52 +/- 0.87 vs. 3.378 +/- 0.83 nM/mg protein, p = 0.04) and correlated negatively to warm ischemia time (R(2)= 0.8022 and R(2)= 0.7996, respectively). Islets from NHBDs took longer to control hyperglycemia in diabetic mice, but were equally able to sustain euglycemia. With a warm ischemia time (WIT) of <or=25 min, islets from NHBDs are at least as competent as islets from BDDs and should be suitable for clinical use.
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PMID:Human islets derived from donors after cardiac death are fully biofunctional. 1784 65

TRPC5 channels are Ca(2+)-permeable nonselective cation channels activated by G-protein-coupled receptors, although the mechanisms responsible for channel activation and regulation are poorly understood. Carbachol-activated TRPC5 currents were recorded by the whole-cell patch clamp technique from human embryonic kidney 293 cells transiently transfected with TRPC5 and the M1 muscarinic receptor. Some published studies of TRPC5 currents have included ATP and/or GTP in the patch pipette, whereas others used an ATP- and GTP-free pipette solution. We initially included these two nucleotides in the patch pipette but found that TRPC5 currents were absent or were very small. Recordings made with an ATP- and GTP-free pipette solution produced large and robust TRPC5 currents. Under these conditions, treatment of cells with Pasteurella multocida toxin, a selective inhibitor of Galpha(q), almost abolished TRPC5 currents indicating that Galpha(q) is necessary for activation of TRPC5 by the M1 receptor. To study the effect of intracellular ATP on TRPC5 channels, an intracellular perfusion system was used. Perfusion of ADP or control pipette solution had no effect, whereas perfusion of ATP or AMP-PNP, a nonhydrolyzable analog of ATP, significantly inhibited TRPC5 currents. Thus, the effects of ATP have structural specificity and probably involve a direct effect on the channel rather than a phosphorylation-mediated effect. The activity of TRPC5 channels may be linked to cellular metabolism via changes in ATP levels and could be involved in Ca(2+) overload occurring after ischemia when ATP is depleted.
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PMID:Inhibition of TRPC5 channels by intracellular ATP. 1792 57


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