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)

Immuno-proteasome is thought to be responsible for the processing of intracellular antigens and is induced when cells are treated with the inflammatory cytokines promoting cellular immunity. We tested the possibility that immuno-proteasome can be up-regulated in renal cells exposed to a long-lasting ischemia and inflammation in an experimental model of two-kidney, one-clip renovascular hypertension in the rat. Western blotting showed that immuno-proteasome subunit, LMP7, was up-regulated in the clipped ischemic kidney that was atrophic, but not in the contralateral unclipped kidney that underwent compensatory hypertrophy. Immunohistochemical analysis revealed that LMP7 was highly expressed in cortical epithelial and endothelial cells of the ischemic kidney. Surprisingly, the second immuno-subunit, LMP2, was almost undetectable, indicating that renal ischemia may induce exclusively the LMP7 subunit. We also found that renal ischemia neither reduced the SDS-stimulated proteasomal activity nor affected a high level of the PA28 activator. Thus, the results provide evidence that LMP7 immuno-subunit is induced in renal cells exposed to a long-lasting renal ischemia and inflammation, and that there is a direct link between LMP induction and renal atrophy. This opens an opportunity to study a role for LMP-containing proteasomes in the kidneys and other organs undergoing reduction in mass in diseases accompanied by a long-lasting ischemia and inflammatory responses.
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PMID:Immuno-proteasome subunit LMP7 is up-regulated in the ischemic kidney in an experimental model of renovascular hypertension. 1676 38

Therapeutic angiogenesis represents a novel approach to treat critical limb ischemia when revascularization is no more an option. The clinical use of the vascular endothelial growth factor is questioned, because of its side effects. This study was designed to identify and characterize human immunodeficiency virus type 1 (HIV-1) Tat-derived peptides based on their pro-angiogenic properties. A series of Tat-derived peptides were synthesized containing mutations in the basic domain. To minimize side effects Tat peptides were selected exerting no effects on the proteasome and on the viability of human umbilical vein endothelial cells (HUVEC). Tatpep5, 15, and 16 increased the endogenous levels of the pro-angiogenic transcription factors c-Jun and SP-1 as well as the production of the plasminogen activator inhibitor-1 (PAI-1) by HUVEC. A significant induction of endothelial cell invasion was observed upon treatment of HUVEC with Tat peptides. In addition, selected Tat peptides induced tube formation by HUVEC as visualized and quantified in a Matrigel matrix. Our data demonstrate that the selected Tat peptides fulfill essential criteria for pro-angiogenic substances. They represent the basis for the development of novel pro-angiogenic drugs for future therapeutic angiogenesis, which might be applied for treatment of unreconstructible critical limb ischemia.
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PMID:Identification of HIV-1 Tat peptides for future therapeutic angiogenesis. 1680 Aug 39

The aim of this study is to investigate the role of proteasome in the pathogenesis of lung injury induced by intestinal ischemia/reperfusion (I/R) by examining the effect of the proteasome inhibitor lactacystin on neutrophil infiltration, intracellular adhesion molecule-1 (ICAM-1) expression and nuclear factor kappa B (NF-kappaB) activation. Thirty-two Wistar rats were divided into (1) control, (2) intestinal I/R, (3) 0.2 mg/kg lactacystin pretreated, and (4) 0.6 mg/kg lactacystin pretreated groups (n=8). Injuries in lung and intestine were induced by intestinal I/R, and were characterized by histological edema, hemorrhage and infiltration of inflammatory cells. The results showed a significant increase in serum creatine kinase B (CK-B) and lung water content in intestine and lung injuries. As compared with the control group, the myeloperoxidase (MPO) activity in intestine and lung as well as the serum TNF-alpha level increased significantly in intestinal I/R group. Simultaneously, expression of ICAM-1 and NF-kappaB p65 was also observed in the I/R group. Pre-treatment with lactacystin markedly reduced 20S proteasome activity in circulating white blood cells and ameliorated intestine and lung injuries. These results demonstrated that the proteasome participates in the pathogenesis of lung injury induced by intestinal I/R. Lactacystin as a proteasome inhibitor can prevent this kind of injury by decreasing ICAM-1 and TNF-alpha production via the inhibition of NF-kappaB activation.
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PMID:Proteasome inhibition attenuates lung injury induced by intestinal ischemia reperfusion in rats. 1687 3

A role of proteasomal proteolysis in the pathogenesis of ischemia-reperfusion is being actively studied. To evaluate the participation of the proteasome in postconditioning phenomenon, we used primary culture of neonatal cardiomyocytes. 30 minutes of anoxia followed by 60 minutes of reoxygenation was undergone. Postconditioning was modeled by 3 cycles of 1-minute reoxygenation followed by 1-minute anoxia, respectively. Clasto-lactacystin b-lactone, a specific proteasome inhibitor, in the dose that does not cause cell death (2.5 mM) was added to the culture medium just before the cycles of postconditioning. Percentages of living, necrotic, and apoptotic cells were determined by staining with bisBenzimide and propidium iodide. Autophagy was demonstrated by staining vacuolar structures with monodansyl cadaverine. Proteasomal activity was determined by cleavage intensity of specific fluorogenic substrates. Trypsin-like, chymotrypsin-like and peptidyl-glutamyl peptide-hydrolyzing (PGPH) activities were decreased after anoxia. Reoxygenation led to an increase in trypsin-like and chymotrypsin-like activities comparing to anoxia, but these parameters never reached the control levels. PGPH activity was restored up to the initial level. Postconditioning increased numbers of living cells and decreased that of necrotic, apoptotic and autophagic cells. Paradoxically, it was established, that proteasome inhibitors prevented the necrotic and apoptotic cell death of cardiomyocytes in anoxia-reoxygenation, but in the same concentration abolished the effects of postconditioning. The data obtained permit to suppose that proteasome inhibitors can be used for pharmacological postconditioning.
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PMID:Proteasome inhibitors eliminate protective effect of postconditioning in cultured neonatal cardiomyocytes. 1690 52

While the role of the ubiquitin-proteasome system (UPS) in regulating cellular processes continues to expand, the elucidation of its role in cardiac disease is just beginning. The UPS regulates pivotal processes at all levels of cardiac biology: from membrane-associated ion channels and receptors to downstream signaling intermediates and transcription factors. Moreover, the role of the UPS in maintaining cardiac protein quality control is emerging, as exemplified by its multiple interactions with the cardiac sarcomere and role in familial cardiomyopathies. The diversity of UPS regulation lies in E3 ligases, which specifically recognize targets and direct the ubiquitination process. In the context of disease, E3 ligase expression affects the severity of disease in both ischemia reperfusion injury and cardiac hypertrophy in vivo by modulating signaling intermediates. In ischemia-reperfusion injury, the activities of CHIP and MDM2 (both with E3 ligase activity) profoundly affect apoptosis regulation and severity of disease. In cardiac hypertrophy, Atrogin1 and MuRF1 attenuate cardiac hypertrophy by interacting with calcineurin and PKCepsilon, respectively. Additionally, MuRF1 and MDM2 interact with sarcomeric proteins (cTnI and Tcap, respectively) which may prove to be mechanisms by which hypertrophy is attenuated or protein quality modulated. All of these exciting new findings, however, must be taken in the context of disease regulation of the UPS components themselves. Key UPS components (e.g. ubiquitin, E1, E2, E3, proteasome) are themselves transcriptionally regulated in cardiac disease. Our understanding of the precise nature by which the UPS regulates key biological functions in cardiac disease has just begun.
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PMID:Into the heart: the emerging role of the ubiquitin-proteasome system. 1694 2

Pyrrolidine dithiocarbamate (PDTC), an inhibitor of nuclear transcription factor kappa-B (NF-kappaB) and an antioxidant, has beneficial effects in animal models of various diseases, including arthritis, brain ischemia, spinal cord injury, Alzheimer's disease, and Duchenne muscular dystrophy. Because inflammation and oxidative damage are also hallmarks of amyotrophic lateral sclerosis (ALS), we studied the effect of oral PDTC treatment on G93A-superoxide dismutase 1 (SOD1) transgenic (TG) rat model of human ALS and observed that PDTC treatment significantly decreases the survival. PDTC treatment evoked the end stage of the disease at 121 +/- 21 days, whereas untreated TG animals reached the end stage at 141 +/- 13 days (p < 0.01). The DNA binding activity of NF-kappaB was not altered in G93A-SOD1 TG rats by PDTC treatment. The copper concentration in the spinal cord was increased after PDTC treatment both in G93A-SOD1 TG and wild-type rats, suggesting that increased copper may enhance the neurotoxicity of mutant SOD1. The amount of ubiquitinated proteins were significantly higher and proteasomal activity was decreased in the spinal cords of PDTC-treated TG rats compared with other groups, suggesting that PDTC treatment decreases proteasome function. Immunoblotting and immunocytochemistry showed that the level of immunoproteasome but not constitutive proteasome was increased in glia of G93A-SOD1 TG rats along with disease development. PDTC treatment completely blocked the induction of immunoproteasome expression without affecting constitutive proteasome. These results suggest that PDTC acts as an immunoproteasome inhibitor in mutant SOD1 rats and that immunoproteasome may help the nervous system to cope with deleterious effects of SOD1-G93A mutation.
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PMID:Pyrrolidine dithiocarbamate inhibits induction of immunoproteasome and decreases survival in a rat model of amyotrophic lateral sclerosis. 1700 87

Dysfunction of the ubiquitin-proteasome system has recently been linked to stroke. Ischemia may cause increased protein misfolding and inhibit the proteasome, shifting the balance from free ubiquitin to conjugated ubiquitin. In this study, we examine the effect of hypothermia on the distribution of total and free ubiquitin, as well as the levels of conjugated ubiquitin after experimental stroke using a focal cerebral ischemia model. We show that hypothermia prevents redistribution of ubiquitin following ischemia, largely through preservation of intracellular cytoplasmic free ubiquitin. We also show that hypothermia blocks the increase in conjugated ubiquitin observed after stroke. Our data indicate that hypothermia's neuroprotection is mediated, in part, through preservation of ubiquitin-proteasome system function.
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PMID:Hypothermia blocks ischemic changes in ubiquitin distribution and levels following stroke. 1704 55

Based on the biological significance of the ubiquitin-proteasome pathway (UPP) and its potential role during sepsis, burns and ischemia-reperfusion injury, we hypothesized that the systemic response to traumatic shock (TS) is accompanied by tissue-specific UPP alterations. Therefore, we studied tissue ubiquitin pools, chymotryptic- and tryptic-like proteasome peptidase activities and ubiquitin-protein ligation (UbPL) rates in skeletal muscle, heart, lung, liver, spleen and kidney using a clinically relevant porcine model (bilateral femur fracture/hemorrhage followed by fluid resuscitation). TS induced a systemic reduction of tissue-specific high molecular mass ubiquitin-protein conjugates (>50 kDa). Free ubiquitin was unaffected. The dynamic organ patterns of ubiquitin pools paralleled the typical physiological response to TS and resuscitation. Reduction of ubiquitin-protein conjugates was most pronounced in heart and lung (p<0.05 vs. control) and accompanied by significant increases in proteasome peptidase and UbPL activities in these organs. Unlike all other tissues, spleen proteasome peptidase and UbPL activities were significantly reduced 10 h after TS. These findings support the concept that the UPP could play an important role in regulation of cell functions during the early whole-body response to TS. The UPP might be a therapeutic target to improve the metabolic care after TS, particularly in the heart, lung, and spleen.
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PMID:Dynamics of tissue ubiquitin pools and ubiquitin-proteasome pathway component activities during the systemic response to traumatic shock. 1718 42

The 26S proteasome is a multicatalytic intracellular protease expressed in eukaryotic cells. It is responsible for selective degradation of intracellular proteins that are responsible for cell proliferation, growth, regulation of apoptosis and transcription of genes involved in execution of key cellular functions. Thus proteasome inhibition is a potential treatment option for cancer and diseases due to aberrant inflammation condition. Treatment with proteasome inhibitors results in stabilization and accumulation proteasome substrates, a phenomenon that may result in confounding signals in cells, cell cycle arrest and activation of apoptotic programs. The inhibition of the transcriptional factor nuclear factor kappaB (NF-kappaB) activation was found as one of crucial mechanisms in induction of apoptosis, overcoming resistance mechanisms and inhibition of immune response and inflammation mechanisms. Bortezomib (PS-341) and PS-519 are the first proteasome inhibitors that have entered clinical trials. In multiple myeloma, both the FDA (United States Food and Drug Administration) and EMEA (European Medicine Evaluation Agency) granted an approval for the use of bortezomib (Velcade) for the treatment of relapsed multiple myeloma. At present, several phase II and phase III trials in hematological malignancies and solid tumors are ongoing. PS-519 that focuses on inflammation, reperfusion injury and ischemia is currently under evaluation for the indication of acute stroke.
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PMID:Proteasome as an emerging therapeutic target in cancer. 1734 44

G protein-coupled receptor kinase 2 (GRK2) modulates G protein-coupled receptor desensitization and signaling. We previously described down-regulation of GRK2 expression in vivo in rat neonatal brain following hypoxia-ischemia. In this study, we investigated the molecular mechanisms involved in GRK2 down-regulation, using organotypic cultures of neonatal rat hippocampal slices exposed to oxygen and glucose deprivation (OGD). We observed a 40% decrease in GRK2 expression 4 h post-OGD. No changes in GRK2 protein occurred after exposure of hippocampal slices to glucose deprivation only. No significant alterations in GRK2 mRNA expression were detected, suggesting a post-transcriptional effect of OGD on GRK2 expression. Blockade of the proteasome pathway by MG132 prevented OGD-induced decrease of GRK2. It has been shown that extracellular signal-regulated kinase-dependent phosphorylation of GRK2 at Ser670 triggers its turnover via the proteasome pathway. However, despite a significant increase of pSer670-GRK2 after OGD, inhibition of the extracellular signal-regulated kinase pathway by PD98059 did neither prevent the hypoxia-ischemia-induced increase in pSer670-GRK2 nor the down-regulation of GRK2 protein. Interestingly, inhibition of phosphoinositide-3-kinase with wortmannin inhibits both OGD-induced phosphorylation of GRK2 on Ser670 and the GRK2 decrease. In conclusion, OGD-induced phosphoinositide-3-kinase-dependent phosphorylation of GRK2 on Ser670 is a novel mechanism leading to down-regulation of GRK2 protein via a proteasome-dependent pathway.
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PMID:Down-regulation of GRK2 after oxygen and glucose deprivation in rat hippocampal slices: role of the PI3-kinase pathway. 1743 35


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