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

Calcium-tolerant rabbit cardiomyocytes were isolated using retrograde aortic perfusion with a nominally calcium-free, collagenase buffer. In vitro ischemic preconditioning was induced by a 10-min episode of ischemic pelleting, followed by a 15-min post-incubation and a prolonged period of ischemic pelleting. Injury was assessed by determination of cell contracture and trypan blue permeability following hypotonic swelling and correlated with metabolic assays of lactate and adenine nucleotides. The protein phosphatase PP1/2A inhibitor calyculin A and PP2A-selective fostriecin protected isolated rabbit cardiomyocytes from lethal injury after a 10-min pre-incubation and when added late into ischemic pellets after a delay of 75 min. At the time of late drug addition, cells were severely ATP-depleted and in rigor contracture. Protection with Calyculin A from 1 nM to 1 microM was dose-related. Cells pre-incubated with 10 nM to 10 microM fostriecin 10 min prior to ischemic pelleting were protected with an EC50 approximating 71 nM, implying protection at a PP2A-selective dose. The selective protein kinase C inhibitor, calphostin C, blocked ischemic preconditioning protection but not protection from 1 microM calyculin A. Protection of severely ischemic cardiomyocytes following protein phosphatase inhibition appears not to require PKC activity or ATP conservation. Pre-incubation of cells with calyculin A induced high levels of phosphorylation in p38 mitogen activated protein kinase (MAPK), as compared to the ischemia-induced phosphorylation observed in the untreated group only at 30 min of ischemia, providing evidence of protein phosphatase activity in cardiomyocytes. Pharmacological protection in late ischemia has been demonstrated, but the mechanism of protection is undetermined.
 ...
PMID:Protein phosphatase inhibitors calyculin A and fostriecin protect rabbit cardiomyocytes in late ischemia. 950 Aug 65

Myocardial infarction results in focal areas of ischemia, hypoxia, necrosis, and decreased contractile function. To compensate for loss of contractile function, remaining viable myocytes undergo hypertrophic growth. Prostaglandin F2alpha (PGF2alpha), which is released from cells of the myocardium during periods of stress such as hypoxia or ischemia/reperfusion, has recently been shown to stimulate hypertrophic growth in neonatal rat ventricular myocytes. In the present study, we determine which growth-related intracellular pathways are required for PGF2alpha to induce morphological and genetic features characteristic of the hypertrophic phenotype. In cardiomyocytes, PGF2alpha increases the hydrolysis of inositol phosphates and induces the translocation of protein kinase C epsilon to the myocyte membrane, consistent with PGF2alpha receptor coupling to Gq. PGF2alpha also activates the extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase pathways. Surprisingly, studies using pharmacological inhibitors and transfection of dominant-interfering proteins demonstrate that PGF2alpha-induced myocyte hypertrophy occurs independent of either PKC, p38, or ERK pathways. Additional studies demonstrate that PGF2alpha stimulates protein tyrosine phosphorylation and activates c-Jun NH2-terminal kinase and suggest that these pathways mediate hypertrophic growth in response to PGF2alpha.
 ...
PMID:Tyrosine kinase and c-Jun NH2-terminal kinase mediate hypertrophic responses to prostaglandin F2alpha in cultured neonatal rat ventricular myocytes. 968 56

Abdominal ischemia reflexly activates the cardiovascular system by stimulating abdominal visceral afferent nerve endings. Whereas many ischemic metabolites responsible for activating these nerves have been identified (e.g., bradykinin), their precise mechanism of action is unclear. Protein kinase C (PKC) is an important part of the signal transduction process underlying the action of metabolites such as bradykinin and is a regulator of neuronal activity. Therefore, we hypothesized that PKC contributes to stimulation of ischemically sensitive abdominal visceral afferents. Single-unit activity was recorded from the right thoracic sympathetic chain of anesthetized cats. Exogenous activation of PKC using phorbol 12, 13-dibutyrate (PDBu, 5 microg/kg ia) increased the impulse activity of ischemically sensitive C-fiber afferents from 0.04 +/- 0.01 to 0. 67 +/- 0.23 impulses/s (n = 11; P < 0.05). The influence of endogenous activation of PKC also was evaluated during 10 min of mesenteric ischemia. Inhibition of PKC using PKC-(19-36) (20 microg/kg iv) reduced ischemia-induced increases in afferent activity from 0.46 +/- 0.11 to 0.19 +/- 0.08 impulses/s (n = 7, P < 0.05). Moreover, PKC-(19-36) (20 microg/kg iv) reduced the response of ischemically sensitive C fibers to bradykinin (0.5-1.0 microg/kg ia) from 1.18 +/- 0.20 to 0.66 +/- 0.14 impulses/s (n = 13, P < 0. 05). These results indicate that PKC contributes to activation of abdominal visceral afferents during ischemia and specifically to part of the bradykinin-induced activation of these afferents.
 ...
PMID:Signal transduction in activation of ischemically sensitive abdominal visceral afferents: role of PKC. 972 9

Stimulation of receptors for alpha 1-adrenergic agonist, endothelin (ET) and angiotensin II (AT) activates the cardiac sarcolemmal Na+/H+ exchanger (NHE), perhaps via protein kinase C(PKC)-mediated pathway(s). We tested for the ability of these extracellular stimuli to exacerbate reperfusion arrhythmias and for the possible role of NHE activation and PKC in such phenomena. Isolated rat hearts (n = 12/group) were subjected to dual coronary perfusion. After 15 min of aerobic perfusion, flow to the left coronary bed was reduced to 5% of basal values for 12 min, and the same bed was then reperfused for 5 min. An alpha 1-adrenergic agonist phenylephrine (PE) at 1 or 10 mumol/L, ET at 0.5 or 5nmol/L or AT at 1 or 10mumol/L was infused selectively into the left coronary bed during 12 min of regional low flow ischemia. The incidence of reperfusion-induced ventricular fibrillation (VF) was increased from 17% in control to 33% and 75%* with 1 and 10 mumol/L PE(*p < 0.05 vs control) from 8% in control to 8% and 12% with 0.5 and 5 nmol/L of ET. However, AT had no effect. The selective NHE inhibitor NOE642 at 1 mumol/L, infused concomitantly with 10 mumol/L PE, reversed the proarrhythmic effects of PE; VF incidence was reduced from 67% to 8%*. However, glibenclamide (a blocker for the ATP-sensitive K+ channel) at 1 mumol/L did not affect the proarrhythmic effects of PE. Infusion of a specific PKC inhibitor GF109203X(GF) at 30 or 300 nmol/L, starting from 5 min before ischemia and maintained throughout ischemia concomitantly with 10 mumol/L of PE, was partially effective in reducing VF incidence; which reduced from 75% in control to 42% with 300 nmol/L of GF. These results suggest that, in rat hearts subjected to regional low-flow ischemia and reperfusion, stimulation of alpha 1-adrenergic receptor can exacerbate reperfusion-induced VF, whose mechanism(s) may involve NHE activation. Moreover, PKC activation does not appear to be the sole signaling mechanism for this phenomenon.
 ...
PMID:[Effect of phenylephrine, endothelin and angiotensin II on reperfusion arrhythmias. A role for Na+/H+ exchanger activation via protein kinase C]. 975 95

Exogenously administered adenosine agonist will protect myocardium against infarction during ischemia. However, long-term exposure to adenosine agonists is associated with loss of this protection. To determine why this protection is lost, isolated, perfused rabbit hearts were studied after administration of R(-)-N6-(2-phenylisopropyl)adenosine (PIA), 0.25 mg/h IP, for 3-4 days to intact animals. All hearts experienced 30 min of regional ischemia and 120 min of reperfusion. Control groups 1 and 2 were untreated. In group 1 this ischemia/reperfusion was the only intervention, whereas group 2 hearts were preconditioned with a cycle of 5 min global ischemia/10 min reperfusion preceding the 30 min regional ischemia. Groups 3-5 had been chronically exposed to PIA. Group 3 hearts had 1 preconditioning ischemia/reperfusion cycle before the prolonged ischemia. Group 4 received a 5 min infusion of 0.1 micromol/L phenylephrine in lieu of global ischemia, whereas group 5 was instead treated with 1 micromol/L carbachol. Infarct size averaged 32% of the risk zone in group 1, whereas ischemic preconditioning limited infarction to 8.2% in group 2. Prolonged exposure of group 3 hearts to PIA resulted in the inability of preconditioning with 5 min global ischemia to protect (28.7+/-4.4% infarction). However, protection was restored by either phenylephrine, an agonist of alpha1-adrenergic receptors which couple to Gq and stimulate PKC, or carbachol, an agonist of M2-muscarinic receptors which couple instead to Gi as do adenosine A1 receptors (5.2+/-1.7% and 9.2+/-2.1% infarction, resp.). Therefore, cross tolerance to ischemic preconditioning develops after chronic PIA infusion. Since both the Gi and the PKC components of the preconditioning pathway were shown to be intact, tolerance must have been related to downregulation or desensitization of the A1 adenosine receptor.
 ...
PMID:Loss of myocardial protection from ischemic preconditioning following chronic exposure to R(-)-N6-(2-phenylisopropyl)adenosine is related to defect at the adenosine A1 receptor. 977 81

Protein kinase C (PKC) has been suggested to mediate, at least in part, multiple processes in the pathophysiological sequelae of myocardial ischemia. The present study demonstrates that the epsilon, eta and iota isozymes of PKC are translocated to nuclei in response to brief intervals of global ischemia as well as reperfusion of ischemic rat myocardium. Concomitant with the translocation of PKC isozymes to nuclei during ischemia, increased PKC-mediated nuclear protein phosphorylation was observed. Taken together, the present results demonstrate that nuclear signaling mechanisms are activated during myocardial ischemia that include PKC translocation and PKC-mediated nuclear protein phosphorylation.
 ...
PMID:Identification of specific nuclear protein kinase C isozymes and accelerated protein kinase C-dependent nuclear protein phosphorylation during myocardial ischemia. 982 54

The current study focuses on the role of p38 MAP kinase in response to acute preconditioning stimuli and ischemia. Exposure of the rat myoblast cell line H9C2 to preconditioning stimuli, viz. brief duration of ischemia (metabolic inhibition) and adenosine, led to activation of p38 MAP kinase. The protective preconditioning effect of these stimuli against lethal ischemic insult was abolished in the presence or p38 MAP kinase inhibitor SB 203580 but not in the presence of MEK inhibitor PD 98509. Phorbol myristate acetate, PMA, which activates protein kinase C, PKC, activates p38 MAP kinase. and this activation is inhibited by PKC inhibitor G. 6850. The preconditioning effect of PMA was abolished by SB 203580 and also by protein kinase C inhibitor Go 6850. This indicates that the protective action of preconditioning by PKC is mediated via activation of p38 MAP kinase. Paradoxically, the presence of SB 203580 and Go 6850 during the lethal stress protected the cells against cell death. The mode of cell death in this study whether necrotic or apoptotic has not been established. Lethal ischemic stress activates p38 MAP kinase. Preconditioning the cells decreases the activation of p38 MAP kinase in response to the second lethal stress. These findings highlight the role of p38 MAP kinase in ischemic preconditioning v ischemia. Furthermore, our findings in an in vitro model using a proliferating cell line indicate that the duration and/or intensity of stimuli activating p38 kinase probably determines whether it would play a beneficial v deleterious role in cell survival in response to stress.
 ...
PMID:Role of p38 MAP kinase in myocardial stress. 984 Dec 66

It is controversial whether nitric oxide (NO) is protective or deleterious against ischemia-reperfusion injury. We examined the effect of NO on PKC isoform translocation and protection against ischemia-reperfusion injury in perfused heart. An NO synthase inhibitor L-NAME (NG-nitro-L-arginine methyl ester, 3.0 microM), administered only during reperfusion but not during ischemia, inhibited the translocation of PKC-alpha, -delta and -epsilon isoforms to the nucleus-myofibril fraction and the translocation of PKC-alpha to the membrane fraction after ischemia (20 min) and reperfusion (10 min) in the perfused rat heart. NO donors, 3-morpholinosydnonimine (SIN-1) or S-nitroso-N-acetylpenicillamine (SNAP) activated purified PKC in vitro. SIN-1 also induced PKC isoform translocation in perfused heart. On the other hand, PKC selective inhibitor, calphostin C (0.2 microM) or chelerythrine (1.0 microM), aggravated the contractile dysfunction of ischemic heart during reperfusion, when they were perfused during reperfusion. These data suggest that NO generated during reperfusion following ischemia activates PKC isoforms and may protect the heart against contractile dysfunction in the perfused rat heart.
 ...
PMID:Nitric oxide mediates protein kinase C isoform translocation in rat heart during postischemic reperfusion. 1003 21

The in vivo state of phosphorylation and the modification of two Cys residues of neuromodulin/ GAP-43 (Nm) were analyzed by electrospray ionization-mass spectrometry (ES-MS). The protein was purified from rat brain with homogenization buffer containing 1% Nonidet P-40, protease inhibitors, protein phosphatase inhibitors, and sulfhydryl reagent, 4-vinylpyridine. Nm was purified by HPLC and ion-exchange chromatography, and the various fractions were identified by ES-MS as unphosphorylated and mono-, di-, tri-, and tetraphosphorylated species. All of these Nm species contained 2 mol of added 4-vinylpyridine per mol of Nm, suggesting that the two Cys residues are in the reduced form in the brain. In vivo, the majority of Nm is in the phosphorylated form (approximately 80%), of which the levels of the mono- and diphospho forms are higher than those of the tri- and tetraphospho species. Four in vivo phosphorylation sites, Ser41, Thr95, Ser142, and Thr172, were identified by amino acid sequencing and tandem ES-MS of the peptides derived from Lys-C endoproteinase digestion. Among these sites, only Ser41 is a known target of PKC, whereas the kinases responsible for the phosphorylation of the other three novel sites are unknown. Hypoxia/ischemia caused a preferential dephosphorylation of Ser41 and Thr172, whereas Thr95 is the least susceptible to dephosphorylation.
 ...
PMID:Hypoxia/ischemia induces dephosphorylation of rat brain neuromodulin/GAP-43 in vivo. 1003 3

The importance of endothelial contraction in the genesis of inflammatory edema has been reported. ROS are metabolites synthesized in pathological conditions in that a significant intravascular fluid leak occurs, such as ischemia-reperfusion. Present experiments were designed to test the hypothesis that ROS, particularly H2O2, may elicit the contraction of endothelial cells, and to explore the mechanisms involved. Bovine aortic endothelial cells incubated with H2O2 showed a significant reduction in planar cell surface area (PCSA), and a significant increase in myosin light chain phosphorylation (MLCP), with a time- and dose-dependent pattern, without any significant toxicity. This effect of H2O2 was not blocked by sulotroban (TxA2 antagonist) or BN 52021 (PAF antagonist). Lanthanum chloride (calcium channel blocker) and EGTA partially inhibited the increase in MLCP induced by H2O2. H7 and staurosporine, PKC inhibitors, and PKC down-regulation (phorbol myristate acetate treatment, 24 h) also blocked H2O2-dependent endothelial contraction, measured as PCSA or MLCP. H2O2 increased the intracellular calcium concentration, an effect blunted by EGTA and lanthanum chloride. H2O2 also increased the phosphorylation of an 80 kD polypeptide, probably MARCKS, a PKC substrate. In summary, the present results demonstrate the ROS-dependent contraction of endothelial cells, an effect that could explain the intravascular fluid leak observed in some pathophysiological situations. Calcium and PKC may be involved in the development of this contraction.
 ...
PMID:Mechanisms involved in the contraction of endothelial cells by hydrogen peroxide. 1021 38


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>