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)

We have established an in vitro model of ischemia incorporating the combination of anoxia with glucose deprivation, which is toxic to PC12 cells. In this model, nerve growth factor (NGF), basic fibroblast growth factor (bFGF), and epidermal growth factor (EGF) improve PC12 cell survival. K252a, a specific inhibitor of NGF-induced trk p140 autophosphorylation, did not alter the neuroprotection provided by EGF or bFGF, yet it completely abolished the protection provided by NGF. Activation of protein kinase A (PKA) with dibutyryl-cAMP also protected during ischemia, although it was not additive with the effect provided by growth factors. Furthermore, growth factors protected a PKA-deficient mutant as effectively as the parental cell line; thus, activation of PKA is protective against ischemia but is not necessary for the action of peptide growth factors. Neither the stimulation of protein kinase C (PKC) with acute phorbol ester treatment nor the downregulation of PKC with chronic high-dose phorbol ester treatment resulted in an altered response to growth factors in either the PC12 wild type or PKA-deficient mutant. Thus, protection by peptide growth factors depends on neither PKA nor PKC. Furthermore, downregulation of PKC alone was protective, indicating that PKC may contribute to toxicity. Interestingly, treatment with the kinase inhibitor H-7 was neuroprotective and may have enhanced the neuroprotective effect of NGF. In contrast, staurosporine, a broadly acting kinase inhibitor, inhibited the neuroprotective effect of NGF, but not of EGF or FGF.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Growth factors protect PC12 cells against ischemia by a mechanism that is independent of PKA, PKC, and protein synthesis. 841 Jan 84

The transcription factors controlling the complex genetic response to ischemia and their modes of regulation are poorly understood. We found that ATF-2 and c-Jun DNA binding activity is markedly enhanced in post-ischemic kidney or in LLC-PK1 renal tubular epithelial cells exposed to reversible ATP depletion. After 40 min of renal ischemia followed by reperfusion for as little as 5 min, binding of ATF-2 and c-Jun, but not ATF-3 or CREB (cAMP response element binding protein), to oligonucleotides containing either an ATF/cAMP response element (ATF/CRE) or the jun2TRE from the c-jun promoter, was significantly increased. Binding to jun2TRE and ATF/CRE oligonucleotides occurred with an identical time course. In contrast, nuclear protein binding to an oligonucleotide containing a canonical AP-1 element was not detected until 40 min of reperfusion, and although c-Jun was present in the complex, ATF-2 was not. Incubating nuclear extracts from reperfused kidney with protein phosphatase 2A markedly reduced binding to both the ATF/CRE and jun2TRE oligonucleotides, compatible with regulation by an ATF-2 kinase. An ATF-2 kinase, which phosphorylated both the transactivation and DNA binding domains of ATF-2, was activated by reversible ATP depletion. This kinase coeluted on Mono Q column chromatography with a c-Jun amino-terminal kinase and with the peak of stress-activated protein kinase, but not p38, immunoreactivity. In conclusion, DNA binding activity of ATF-2 directed at both ATF/CRE and jun2TRE motifs is modulated in response to the extreme cellular stress of ischemia and reperfusion or reversible ATP depletion. Phosphorylation-dependent activation of the DNA binding activity of ATF-2, which appears to be regulated by the stress-activated protein kinases, may play an important role in the earliest stages of the genetic response to ischemia/reperfusion by targeting ATF-2 and c-Jun to specific promoters, including the c-jun promoter and those containing ATF/CREs.
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PMID:Ischemia and reperfusion enhance ATF-2 and c-Jun binding to cAMP response elements and to an AP-1 binding site from the c-jun promoter. 853 Apr 13

Adenosine functions as a counterregulatory hormone in the myocardium by decreasing work and thereby protecting the myocardium against ischemia. Functional adenosine A1 receptors could serve as an important regulatory system in the developing preinnervated heart by balancing the humoral sympathetic input to the heart. The aims of this study were to determine if A1 adenosine receptors were functionally coupled to their Gi protein in the immature preinnervated heart and to determine if A1 adenosine receptors were present in greater numbers in the immature heart. One- to 3-day-old rat ventricular cardiomyocyte cultures were exposed to (1) control conditions; (2) isoproterenol, a beta-receptor agonist, (3) R-PIA, an A1 agonist, or (4) isoproterenol and R-PIA, cAMP levels were determined by RIA in each group. Adenosine A1 receptor density and the equilibrium dissociation constant were determined by binding of an adenosine A1 receptor antagonist in newborn, 1-week-old, 2-week-old, and adult rat hearts. A1 stimulation decreased the isoproterenol-induced increase in cAMP by 30%, demonstrating functional A1 receptors in immature preinnervated myocytes. The A1 receptor density in the newborn age group was twice the adult and 2-week-old level. We conclude that A1 receptors in the immature heart are functionally coupled to their effector and that A1 receptors are present in greater numbers in the immature heart.
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PMID:Ontogeny of rat myocardial A1 adenosine receptors. 853 70

Hypoxia is a common denominator of ischemic microenvironments. Endothelium subjected to oxygen deprivation maintains cell viability and basic biosynthetic mechanisms, but displays multiple changes in properties relevant to vascular homeostasis, including suppression of the anticoagulant cofactor thrombomodulin, decreased barrier function, and generation of proinflammatory cytokines. Diminished intracellular cAMP during the period of hypoxia and lowered nitric oxide/cGMP in the subsequent reperfusion period are proposed as fundamental mechanisms driving vascular dysfunction impacting on coagulation, permeability, vasomotor tone and leukocyte adhesivity. The period of organ preservation for transplantation, recognized to be associated with hypoxia, primes mechanisms leading to subsequent vascular dysfunction which can be ameliorated by buttressing cAMP and nitric oxide/cGMP intra- and intercellular second messenger systems. A mechanism likely to contribute to hypoxia-mediated generation of cytokines, such as interleukin 6, is activation of the transcription factor NF-IL-6, which occurs in oxygen deprivation. These data indicate that study of cellular mechanisms of endothelial perturbation in hypoxia is likely to provide insights ultimately applicable to ischemia-induced vascular damage.
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PMID:Hypoxia and modification of the endothelium: implications for regulation of vascular homeostatic properties. 856 21

In spite of optimal organ preservation techniques, the heart and the lungs remain extremely vulnerable to the ischemia and reperfusion which accompany the transplantation procedure. Following a period of prolonged preservation, the altered phenotype of the graft vasculature results in vasoconstriction, neutrophil sequestration, edema, and thrombosis in the reperfused graft. These parameters of vascular dysfunction translate into primary graft failure and recipient demise. Using endothelial cells exposed to hypoxia and reoxygenation as a simple paradigm for the vascular milieu during organ preservation/transplantation, we have found that second messenger pathways (cAMP and NO/cGMP) are suppressed, neutrophil-endothelial interactions are enhanced, and prothrombotic mechanisms are activated. Using heterotopic rat heart and orthotopic rat lung transplant models, we have shown that supplemention of second messenger pathways or interference with neutrophil-endothelial interactions can significantly enhance preservation. Understanding mechanisms of vascular dysfunction within the graft should help define clinically relevant therapeutic targets to enhance heart or lung preservation for transplantation.
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PMID:The vascular biology of heart and lung preservation for transplantation. 857 26

Reduction of cAMP has been implicated in the protection of ischemic preconditioning (IP), but until now, this possibility has not been directly addressed. In this study, we found that in the in vivo rabbit heart 10 to 30 minutes of sustained regional ischemia was accompanied by a nearly twofold rise in cAMP levels. This increase in cAMP was attenuated when sustained ischemia was preceded by IP induced with a single cycle of transient ischemia and reperfusion (TI/R) and prevented when ischemia was preceded by three cycles of TI/R. The mechanism of cAMP reduction by IP does not involve activation of protein kinase C (PKC), since the PKC inhibitor polymyxin B (24 mg/kg) did not raise cAMP levels during sustained ischemia in IP hearts. Furthermore, this effect is also not mediated by reduced responsiveness of the beta-adrenergic effector pathway, since both nonischemic hearts and hearts subjected to three cycles of TI/R exhibited similar increases in cAMP in response to 5 micrograms/kg isoproterenol. However, propranolol (0.75 mg/kg) abolished the rise in cAMP levels observed during sustained ischemia in control hearts but did not reduce cAMP levels further in IP hearts. These data indicate that the ischemia-induced rise in cAMP levels in control hearts was mediated by activation of the beta-adrenergic receptor. Taken together with data demonstrating that beta-adrenergic responsiveness was not affected by IP, these data support the conclusion that the lack of elevation in cAMP levels observed during sustained ischemia in IP hearts is mediated by an attenuation of norepinephrine release. To examine whether the protection of IP against necrosis was mediated by the lack of elevation in cAmp levels, we determined whether the infarct size-limiting effect of IP could be blocked by NKH477, an activator of adenylyl cyclase. Four groups or rabbits were subjected to 30 minutes of in vivo regional ischemia and 90 minutes of reperfusion. Control hearts (n = 10) had 53.6 +/- 5.5% infarction of the area at risk. IP with three cycles of transient ischemia limited infarct size to 3.2 +/- 1.3% (N = 13, p < .0001). NKH477 (45 micrograms/kg) increased average cAMP levels in IP hearts during sustained ischemia to levels similar to those in untreated control hearts. However, NKH477 did not block IP (50.2 +/- 7.7% of the area at risk was infarcted in the control +NKH477 group [n = 10] versus 10.0 +/- 5.9% in the IP + NKH477 group [n = 7], P < .05). Therefore, we conclude that although IP lowers cAMP levels during sustained ischemia, this effect is not necessary for its protection against necrosis, since raising cAMP does not block this protection of IP.
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PMID:Effect of ischemic preconditioning of the myocardium on cAMP. 860 96

In many diseases, tissue hypoxia occurs in conjunction with other inflammatory processes. Since previous studies have demonstrated a role for leukocytes in ischemia/reperfusion injury, we hypothesized that endothelial hypoxia may "superinduce" expression of an important leukocyte adhesion molecule, E-selectin (ELAM-1, CD62E). Bovine aortic endothelial monolayers were exposed to hypoxia in the presence or absence of tumor-necrosis factor alpha (TNF-alpha) or lipopolysaccharide (LPS). Cell surface E-selectin was quantitated by whole cell ELISA or by immunoprecipitation using polyclonal anti-E-selectin sera. Endothelial mRNA levels were assessed using ribonuclease protection assays. Hypoxia alone did not induce endothelial E-selectin expression. However, enhanced induction of E-selectin was observed with the combination of hypoxia and TNF-alpha (270% increase over normoxia and TNF-alpha) or hypoxia and LPS (190% increase over normoxia and LPS). These studies revealed that a mechanism for such enhancement may be hypoxia-elicited decrements in endothelial intracellular levels of cAMP (<50% compared with normoxia). Addition of forskolin and isobutyl-methyl-xanthine during hypoxia resulted in reversal of cAMP decreases and a loss of enhanced E-selectin surface expression with the combination of TNF-alpha and hypoxia. We conclude that endothelial hypoxia may provide a novel signal for superinduction of E-selectin during states of inflammation.
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PMID:Hypoxia enhances stimulus-dependent induction of E-selectin on aortic endothelial cells. 869 47

Inositol levels have been studied in cellular cultures and recently by perfusion of isolated hearts. The study was aimed to assess inositol turnover in rabbit hearts from intact animals. Thirty rabbits were injected i.v. three times (every 12 hr) with 25 microCi/kg of myo-3H-inositol. The rabbits 12 hr after the last injection were killed and the hearts perfused according to Langerdorff technique. Systolic and diastolic ventricular pressures (SVP, DVP), dp/dt, and coronary flow (CFl) were measured. The hearts (n = 14) were perfused under aerobic conditions and 16 hearts under ischemic conditions for 30 min. In addition, 5 hearts were perfused under aerobic conditions for 10 min, and 6 hearts were perfused under ischemic conditions for 10 min. Samples of myocardial tissue were taken from both groups at the end of 10-min and 30-min period of perfusion, and cAMP and inositol phosphates were assayed. The hearts subjected to ischaemia showed changes of cAMP and 3H-inositol. The cAMP was higher in the ischaemic (10 min and 30 min) than the control hearts, 0.22 +/- 0.09 and 0.21 +/- 0.08 versus 0.41 +/- 0.12 and 0.49 +/- 0.11 pmol 10(6) cells, respectively (p < .05, p < .001. The inositol trisphosphate was higher in control than ischemic hearts (10 min, 30 min), 0.42 +/- 0.02 and 0.39 +/- 0.01 versus 0.31 +/- 0.01 and 0.23 +/- 0.02 (percent of radioactivity) respectively, p < .001. Our data suggest that 3H-inositol may be studied by i.v. administration to intact animals. The ischemia was performed to verify the validity of this new technique.
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PMID:A new method to measure cardiac inositol levels in intact animals. 872 37

Dibutyryl cAMP (DBcAMP) has a high membrane permeability, and maintenance of the intracellular cAMP concentration may improve the viability of organs. In this study, the effect of DBcAMP pretreatment on warm ischemic injury of rat livers was evaluated. Warm ischemic liver injury was induced in adult Wistar rats weighing 250-280 g by leaving them at room temperature (22-25 degrees C) after cardiac arrest. The hepatic cAMP concentration, %ATP, and trypan blue-positive nuclear ratio were determined after different durations of warm ischemia. In addition, transaminase and endothelin-1 (ET-1) release into the perfusate were examined during 60 min of isolated liver perfusion with Krebs-Henseleit solution. The optimal dose and time of DBcAMP pretreatment were determined to be 15 mg/kg and 60 min prior to warm ischemia, respectively. Data on the trypan blue-positive nuclear ratio and the release of transaminases and ET-1 revealed that warm ischemia first damaged the endothelial cells and then the hepatocytes. DBcAMP pretreatment appeared to protect the liver from warm ischemic injury by increasing the intracellular cAMP concentration and stabilizing the cell membranes of endothelial cells and hepatocytes.
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PMID:The beneficial effect of dibutyryl cyclic adenosine monophosphate on warm ischemic injury of the rat liver induced by cardiac arrest. 875 11

The protein serine/threonine kinases which are highly expressed in the central nervous system (CNS) are severely affected by brain ischemia. Irrespective of substantial differences among the particular members of this group of kinases, their responses to ischemic stress show a lot of similarities. Initially they are switched on by facilitated interaction with their specific activators/second messengers like cyclic AMP, 1,2-sn-diacylglicerol and particularly Ca2+, then they are translocated to highly specific regions of plasma membranes. After phosphorylation of target proteins, the kinases are deactivated by means of different routes. Activity of PKA is regulated by its direct access to cAMP. In the case of CaMKII, it is probably achieved by its extensive, inhibitory autophosphorylations, while PKC seems to be proteolytically degraded. These biphasic changes in serine/threonine kinases activity may play a critical role in the evolution of postischemic brain injury and provide a mechanism for a variety of short- and long-term signalling events.
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PMID:Protein serine/threonine kinases (PKA, PKC and CaMKII) involved in ischemic brain pathology. 876 9


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