Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

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

Ischemia followed by reperfusion in the presence of polymorphonuclear leukocytes (PMNs) results in cardiac contractile dysfunction as well as myocardial injury. These effects are due in large part to endothelial dysfunction leading to an upregulation of cell adhesion molecules and subsequent neutrophil induced cardiac injury. The proteasome inhibitor, PS-519, has been shown to attenuate leukocyte-endothelial cell interactions. We tested the effects of PS-519 on neutrophil mediated cardiac dysfunction in ischemia/reperfusion. This study examines the effects of PS-519 in a neutrophil dependent isolated perfused rat heart model of ischemia (I) (20 min) and reperfusion (R) (45 min). Administration of PS-519 (0.01, 0.1, 0.3, 1.0 mg/kg) to I/R hearts perfused with PMNs improved coronary flow, and preserved left ventricular developed pressure (LVDP) and + dP/dt max as indices of cardiac contractile function. At 1.0 mg/kg, PS-519 treated hearts exhibited a final LVDP of 98 +/- 3% of initial compared to 52 +/- 8% in I/R hearts receiving only vehicle (P < 0.001). In addition, PS-519 significantly reduced PMN accumulation in the ischemic myocardium from 25.1 +/- 2.1 PMNs/mm2 in untreated hearts to 7.3 PMNs/mm2, and attenuated P-selectin surface expression on coronary vascular endothelium from 7.1 +/- 0.3% to 1.4 +/- 0.2% (P < 0.01). These results provide evidence that PS-519 is a potent and effective cardioprotective agent that inhibits P-selectin leukocyte-endothelial cell interactions and preserves cardiac contractile function and coronary perfusion following myocardial ischemia and reperfusion.
...
PMID:Cardioprotective effects of a novel proteasome inhibitor following ischemia and reperfusion in the isolated perfused rat heart. 1009 58

Acute renal failure was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function parameters such as blood urea nitrogen, plasma creatinine, creatinine clearance, urine flow and urinary osmolality were measured to test the effectiveness of drugs. Renal function in untreated acute renal failure rats markedly decreased at 24 h after reperfusion. The administration of PSI, N-benzyloxycarbonyl-Ile-Glu(O-t-Bu)-Ala-leucinal, a proteasome inhibitor, at a dose of 1 mg/kg before the occlusion abolished the decreases in the renal function of acute renal failure rats. Calpeptin (1 mg/kg), a calpain inhibitor, attenuated the deterioration of renal function to the same extent as 0.1 mg/kg PSI, but no significant difference was observed between the untreated and calpeptin-treated acute renal failure groups. Histopathological examination of the kidney of untreated acute renal failure rats revealed severe lesions, such as tubular necrosis, proteinaceous casts in tubuli and medullary congestion, all of which were significantly suppressed by PSI (1 mg/kg) treatment. In contrast, calpeptin, at the same dose, was ineffective against the development of renal lesions. These results suggest that proteasome participates in the pathogenesis of ischemic acute renal failure. Thus, proteasome may be a potential target for the identification of agents that may be useful in the treatment of diseases whose etiology is dependent on ischemia/reperfusion.
...
PMID:Proteasome participates in the pathogenesis of ischemic acute renal failure in rats. 1061 18

The objectives of this study were (1) to assess the role of a proteasome-dependent proteolytic pathway in the pathogenesis of acute renal failure (ARF) induced by ischemia-reperfusion, and (2) to determine the involvement of this proteolytic pathway in the enhanced production of renal endothelin-1 (ET-1) in this model of ARF. ARF was induced by clamping the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function parameters such as blood urea nitrogen, plasma creatinine, creatinine clearance, urine flow, urinary osmolality and fractional excretion of sodium were measured to test the effectiveness of drugs used. Renal function in untreated ARF rats markedly decreased at 24 h after reperfusion. In addition, a marked increase in renal ET-1 content was evident in the ARF rats, compared to the sham-operated rats. Intraperitoneal injection of a proteasome inhibitor (PSI), N-benzyloxycarbonyl-Ile-Glu(O-t-Bu)-Ala-leucinal, at a dose of 1 mg/kg, 1 h before the clamping, significantly attenuated the renal function impairment in the ischemic ARF rats, and the effect was accompanied by a decrease in renal ET-1 content. On the other hand, a calpain inhibitor, calpeptin, had little effect at the same dose. These results suggest that a proteasome-dependent proteolytic pathway is involved in the enhanced production of ET-1 in the kidney and the consequent renal functional damage in ischemic ARF.
...
PMID:Proteasome inhibition attenuates renal endothelin-1 production and the development of ischemic acute renal failure in rats. 1107 83

To elucidate the role of a proteasome-dependent proteolytic pathway in the pathogenesis of acute renal failure (ARF), we examined the effect of a selective proteasome inhibitor, lactacystin, on ARF induced by ischemia/reperfusion. Ischemic ARF was induced by clamping the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function in untreated ARF rats markedly decreased at 24 h after reperfusion. Intraperitoneal injection of lactacystin at a dose of 0.1 mg/kg before the occlusion tended to attenuate the deterioration of renal function. The higher dose of lactacystin (1 mg/kg) markedly attenuated the ischemia/reperfusion-induced renal dysfunction. Histopathological examination of the kidney of untreated ARF rats revealed severe lesions, such as tubular necrosis, proteinaceous casts in tubuli, and medullary congestion, all of which were markedly suppressed by the higher dose of lactacystin. In addition, endothelin (ET)-1 content in the kidney after the ischemia/reperfusion was significantly increased, being the maximum level at 6 h after the reperfusion, and this elevation was abolished by the higher dose of lactacystin. These results indicate that lactacystin prevents the development of ischemia/reperfusion-induced ARF, and the effect is accompanied by suppression of the enhanced ET-1 production in the kidney, thereby suggesting that a proteasome-dependent proteolytic pathway has a crucial role in the pathogenesis of ischemic ARF, possibly through the enhancement of ET-1 production in postischemic kidneys.
...
PMID:Preventive effect of lactacystin, a selective proteasome inhibitor, on ischemic acute renal failure in rats. 1145 11

Secondary brain injury due to ischemia includes the infiltration of leukocytes into the brain parenchyma mediated by activation of nuclear factor-kappaB (NF-kappaB), which is activated by proteasome degradation. Neuroprotection with the proteasome inhibitor MLN519 has previously been reported to decrease ischemic brain injury in rats. The authors used higher doses of MLN519 to evaluate the neuroprotection therapeutic window after 24 hours of brain injury in rats as correlated to proteasome levels, activated NF-kappaB immunoreactivity, and leukocyte infiltration. Male Sprague-Dawley rats were subjected to 2-hour middle cerebral artery occlusion (MCAO) and recovery. MLN519 or vehicle was administered after injury with a single injection given in delayed increments of 2 hours (i.e., 4, 6, or 8 hours after MCAO). Treatment with MLN519 up to 6 hours after MCAO (4 hours after reperfusion) effectively reduced neuronal and astrocytic degeneration, decreased cortical infarct volume, and increased neurologic recovery. These effects were related to >80% reductions in blood proteasome levels, reduced neutrophil infiltration, and a decrease in activated NF-kappaB immunoreactivity. This improved neuroprotection profile and antiinflammatory effect of MLN519 provides an exciting avenue for potential treatment of focal ischemic brain injury in humans.
...
PMID:Delayed treatment with MLN519 reduces infarction and associated neurologic deficit caused by focal ischemic brain injury in rats via antiinflammatory mechanisms involving nuclear factor-kappaB activation, gliosis, and leukocyte infiltration. 1250 93

The haemorrhagic transformation in ischemic stroke involves disruption of the integrity of the microvascular beds, partially based on the action of matrix metalloproteinases (MMPs). The objective of the present study was to evaluate the contribution of microvascular endothelial cells from human brain (HBECs) to MMPs' expression and regulation under conditions relevant to brain ischemia. MMPs and their inhibitors were examined with zymography, Western-blotting, ELISA and MMP-activity assay in cultured HBECs. Four-hour hypoxia (pO(2)=60 mmHg) elevated the level of MMP-9 in the supernatant of the HBECs and this early response required collagen-matrix. Active oxygen species sustained the increased MMP-9 activity for at least 24 h. In the post-hypoxic period 20 micro mol/L H(2)O(2) caused a 6-fold increase in the specific activity of MMP-9 over the normoxic cells and a comparable effect was exerted by thrombin (50 nmol/L) and leukocyte elastase (10 nmol/L). The role of NF-kappaB, a redox-state sensitive transcription factor, was evaluated with immunofluorescence confocal microscopy and immunoblotting of nuclear and cytoplasmic extracts. The oxidative stress-dependent MMP-9 induction was accompanied by a significant increase in the NF-kappaB localized in the nuclei and these responses were blunted with a proteasome inhibitor (MG132). Consequently, according to our in vitro data HBECs are a source of MMP-9, which is under the control of triggers relevant to the ischemic/reperfused brain (reactive oxygen species, thrombus and inflammation related proteases) and this regulation is partially based on NF-kappaB activation. The reported regulation of endothelium-derived MMP-9 supports its potential involvement in the post-hypoxic disturbances of the cerebral microcirculation.
...
PMID:Matrix metalloproteinase-9 expression in post-hypoxic human brain capillary endothelial cells: H2O2 as a trigger and NF-kappaB as a signal transducer. 1295 23

Connexin 43 (Cx43), a primary component of gap junctions, contributes to intercellular electrochemical communication. Cx43 undergoes dephosphorylation in early ischemia. We examined whether Cx43 is degraded in association with dephosphorylation during early myocardial ischemia and whether ischemic preconditioning (IP) affects the degradation after rat coronary artery occlusion. Male Sprague-Dawley rats underwent coronary artery occlusion for 1, 2, or 3 hours, or for 1 hour following treatment either with a calcineurin inhibitor (cyclosporine A), proteasome inhibitor (PSI), or lysosomal inhibitor (E64c), or following IP alone or after protein kinase C (PKC) inhibitor (chelerythrine) pretreatment. The IP was afforded by three cycles of 3 minute ischemia and 5 minute reperfusion. A large portion of the phosphorylated Cx43 (pCx43) in the membrane fraction was dephosphorylated, while a small portion was degraded at 1 hour of ischemia. The effects of the inhibitors were dephosphorylation and degradation by calcineurin and proteasome/lysosome, respectively. IP suppressed the decrease in pCx43 and increase in dCx43, while only the former was inhibited by the PKC inhibitor chelerythrine. The Cx43 mRNA level was reduced at 3 hours, but not at 1 hour of ischemia, irrespective of IP. We believe that Cx43 is dephosphorylated and degraded in early ischemia, whereas Cx43 transcription was suppressed at a later phase of ischemia.
...
PMID:Down-regulation of connexin43 in early myocardial ischemia and protective effect by ischemic preconditioning in rat hearts in vivo. 1565 76

ATP-sensitive K+ channels (K(ATP):SUR2A+Kir6.2) play a pivotal role in cardiac protection against ischemia and reperfusion injury. When expressed in COS cells, Kir6.2 was short-lived with a half-life time of 1.9 h. The half-life time of Kir6.2 was prolonged by proteasome inhibitors MG132, ALLN, proteasome inhibitor 1, and lactacystine, but not at all by a lysosomal inhibitor chloroquine. MG132 also increased the level of ubiquitinated Kir6.2 without affecting its localization in the endoplasmic reticulum and Golgi apparatus. In electrophysiological recordings, MG132 augmented nicorandil-activated K(ATP) currents in COS cells expressing SUR2A and Kir6.2 as well as the same currents in neonatal rat cardiomyocytes. Like MG132, a Na+ channel blocker aprindine prolonged the half-life time of Kir6.2 and augmented K(ATP). Finally, both aprindine and MG132 inhibited the 20S proteasome activity in vitro. These results suggest a novel activity of aprindine to enhance K(ATP) currents by inhibiting proteasomal degradation of Kir 6.2 channels, which may be beneficial in the setting of cardiac ischemia.
...
PMID:Proteasomal degradation of Kir6.2 channel protein and its inhibition by a Na+ channel blocker aprindine. 1588 77

This study examined the hypothesis that postischemic levels of oxidized and/or ubiquitinated proteins may be predictive of functional recovery as they may be indicative of activity of the 20S and/or 26S proteasomes, respectively. Subjecting isolated rat hearts to 15 min of ischemia had no effect on 20S- and 26S-proteasome activities; however, both were significantly (p < 0.05) decreased by 70% and 54%, respectively, following 30 min of ischemia and 60 min of reperfusion, changes associated with increased levels of protein carbonyls and ubiquitinated proteins. Preischemic treatment of hearts with the proteasome inhibitor, MG132, resulted in dose-dependent decreases (p < 0.05) in recovery of postischemic function [MG132 (microM), heart rate x pressure product: 0, 11,158 +/- 2,423; 6, 11,400 +/- 3,009; 12, 5,513 +/- 2,225; 25, 2,325 +/- 992] and increased accumulation of ubiquitinated proteins. Preconditioning with repetitive ischemia (IP) or preischemic treatment with nicorandil (Nic) resulted in a significant increase in postischemic 20S-proteasome activity after 60 min of reperfusion (control, 95 +/- 4; IP, 301 +/- 65; Nic, 242 +/- 61 fluorescence units). Only Nic had similar effects on 26S-proteasome activity. These results support the conclusion that a correlation exists between eventual recovery of postischemic function and levels of oxidized and/or ubiquitinated proteins, a phenomenon that may be dependent on activity of the 20S and 26S proteasomes.
...
PMID:Oxidized and ubiquitinated proteins may predict recovery of postischemic cardiac function: essential role of the proteasome. 1588 99

Ischemic preconditioning (IPC), a brief period of ischemia and reperfusion (I/R), generates profound but transient protection against a subsequent prolonged ischemic episode. The serine-threonine kinase Akt has been shown to mediate IPC, and Akt activation is negatively regulated by the phosphatase PTEN, but whether PTEN activity is modulated by IPC has not been investigated. When isolated, perfused rat hearts were subjected to an IPC stimulus consisting of 15-minute ischemia and 30-minute reperfusion (I-15/R-30), PTEN protein levels and activity were decreased, and levels of phospho-AKT were increased, relative to nonischemic hearts. Hearts subjected to IPC demonstrated improved recovery of cardiac function when subsequently subjected to I-30/R-45 as compared with hearts subjected to I-30/R-45 without prior IPC. When hearts were subjected to I-15 followed by R-30, R-60, or R-120, PTEN reaccumulated gradually and its activity was restored. Phospho-Akt levels at R-120 were decreased and these hearts were no longer protected against injury when subjected to I-30/R-45. Wortmannin administration during reperfusion blocked Akt activation and PTEN reaccumulation. In ischemic hearts, PTEN was rapidly degraded. Pretreatment with proteasome inhibitor MG132 blocked ischemia-induced degradation of PTEN and blocked IPC. Reperfusion following I-15 induced oxidation of the remaining PTEN, leading to Akt activation. Perfusion of H2(O2) was sufficient to induce Akt activation. Thus, loss of PTEN activity leads to induction of IPC and feedback mechanisms designed to ensure that Akt activation is transient are responsible for decay of IPC.
...
PMID:PTEN activity is modulated during ischemia and reperfusion: involvement in the induction and decay of preconditioning. 1691 96


1 2 3 4 5 Next >>

---