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

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Query: EC:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mitochondrial dysfunction is a common consequence of ischemia-reperfusion and drug injuries. For example, sublethal injury of renal proximal tubular cells (RPTCs) with the model oxidant tert-butylhydroperoxide (TBHP) causes mitochondrial injury that recovers over the course of six days. Although regeneration of mitochondrial function is integral to cell repair and function, the signaling pathway of mitochondrial biogenesis following oxidant injury has not been examined. A 10-fold overexpression of the mitochondrial biogenesis regulator PPAR-gamma cofactor-1alpha (PGC-1alpha) in control RPTCs resulted in a 52% increase in mitochondrial number, a 27% increase in respiratory capacity, and a 30% increase in mitochondrial protein markers, demonstrating that PGC-1alpha mediates mitochondrial biogenesis in RPTCs. RPTCs sublethally injured with TBHP exhibited a 50% decrease in mitochondrial function and increased mitochondrial autophagy. Compared with the controls, PGC-1alpha levels increased 12-fold on days 1, 2, and 3 post-injury and returned to base line on day 4 as mitochondrial function returned. Inhibition p38 MAPK blocked the up-regulation of PGC-1alpha following oxidant injury, whereas inhibition of calcium-calmodulin-dependent protein kinase, calcineurin A, nitric-oxide synthase, and phosphoinositol 3-kinase had no effect. The epidermal growth factor receptor (EGFR) was activated following TBHP exposure, and the EGFR inhibitor AG1478 blocked the up-regulation of PGC-1alpha. Additional inhibitor studies revealed that the sequential activation of Src, p38 MAPK, EGFR, and p38 MAPK regulate the expression of PGC-1alpha following oxidant injury. In contrast, although Akt was activated following oxidant injury, it did not play a role in PGC-1alpha expression. We suggest that mitochondrial biogenesis following oxidant injury is mediated by p38 and EGFR activation of PGC-1alpha.
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PMID:Signaling of mitochondrial biogenesis following oxidant injury. 1711 59

Increased organ ischemia time leads to delayed graft function (DGF), increased acute rejection (AR), enhanced chronic allograft nephropathy (CAN), and reduced long-term allograft survival. The mechanisms by which IRI predisposes to AR and CAN are unknown. We hypothesized that gene expression profiling of ischemia-reperfusion injury (IRI)-affected kidney would identify how IRI predisposes to AR and CAN. Furthermore, we examined how current immunosuppressive drug molecular targets are altered by IRI. C57BL/6J mice were exposed to 30 (n = 3) or 60 (n = 3) minutes of bilateral kidney ischemia or sham surgery (n = 5). At 36 hour kidney tissue was collected and analyzed using Affymetrix 430MOEA (22626 genes) array and GC-RMA-SAM pipeline. Genes with the false discovery rate (q < 1%) and +/-50% fold change (FC) were considered affected by IRI. Genes coding for histocompatibility and antigen-presenting factors, calcineurin, and mammalian target of rapamycin (mTOR) pathway-associated proteins were selected using Gene Ontology (GO) analysis. GO analysis identified 10 and 17 alloimmunity-related genes affected by IRI induced by 30 and 60 minutes of ischemia, respectively, including Traf6 (FC = 2.99) and H2-D1 (FC = 2.58). We also detected significant IRI genomic responses in calcineurin and mTOR pathways represented by Fkbp5 (FC = 4.18) and Fkbp1a (FC = 2.0), and Eif4ebp1 (FC = 16.8) and Akt1 (FC = 3.64), respectively. These data demonstrated that IRI up-regulates expression of several alloimmunity-associated genes, which can in turn enhance alloimune responses. Our discovery of IRI-induced up-regulation of genes associated with calcineurin and mTOR pathways are consistent with clinical observations that FK506 and Rapamycin can alter the course of DGF. Further validation and dissection of these pathways can lead to novel approaches by which improved management of early "nonimmune" transplant events can decrease susceptibility to more classic "immune" changes and CAN.
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PMID:Genomic profiling of kidney ischemia-reperfusion reveals expression of specific alloimmunity-associated genes: Linking "immune" and "nonimmune" injury events. 1717 65

Oxidative stress after cerebral ischemia and reperfusion activates extracellular signal-regulated kinases (ERK) in brain. However, the mechanism of this activation has not been elucidated. We have previously reported that in an in vitro model of oxidative stress in immature cortical neuronal cultures, the inhibition of ERK phosphatase activity contributes to ERK1/2 activation and subsequent neuronal toxicity. This study examined whether ERK activation was associated with altered activity of ERK phosphatases in a rat cardiac arrest model. Rats in experimental groups were subjected to asphyxial cardiac arrest for 8 min and then resuscitated for 30 min. Significant ERK activation was detected in both cortex and hippocampus following ischemia/reperfusion by immunoblotting. ERK phosphatase activity was reversibly inhibited in cerebral cortex but not affected in hippocampus following ischemia/reperfusion. MEK1/2 was activated in both cerebral cortex and hippocampus following ischemia/reperfusion. Using a specific inhibitor of protein phosphatase 2A (PP2A), okadaic acid (OA), we have identified PP2A to be the major ERK phosphatase that is responsible for regulating ERK activation in ischemic brain tissues. Orthovanadate inhibited ERK phosphatase activity in brain tissues, suggesting that tyrosine phosphatases and dual specificity phosphatases may also contribute to the ERK phosphatase activity in brain tissues. Together, these data implicate ERK phosphatase in the regulation of ERK activation in distinct brain regions following global ischemia.
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PMID:Different mechanisms account for extracellular-signal regulated kinase activation in distinct brain regions following global ischemia and reperfusion. 1720 79

Post-transplantation diabetes (PTD) is a serious complication in organ transplantation: not only does it increase the risk of graft dysfunction; it also increases cardiovascular morbidity and mortality. PTD incidence is correlated with age, non-Caucasian ethnic background, a family history of diabetes, excess weight, hepatitis C infection and steroid boluses for potential rejection. Different mechanisms might explain post-transplantation glucose metabolism disorders: ischemia-reperfusion disorders, whether renal, hepatic or cardiac, are responsible for insulin-resistance, which is increased by post-transplantation steroids; the detrimental effect of non-steroid immunosuppressive drugs on insulin-secretion could also be involved, especially with calcineurin inhibitors. In vivo and in vitro studies have shown that tacrolimus has inhibitory effects on insulin-secretion, while these effects are less obvious for cyclosporin, and were mainly demonstrated in vitro. Mycophenolate has no overt effect on insulin-secretion. Sirolimus and everolimus, two mTOR inhibitors, have shown controversial results in this realm. The effects of sirolimus (most often studied mTOR inhibitor) appear to depend on serum levels, cell type (ss cell or cell line), species (human or animal) and also environmental nutrients. At therapeutic concentrations, a stimulatory effect on insulin secretion was observed on human beta cells. This might explain the success of islet cell transplantation with the Edmonton protocol. Finally, steroids are mainly detrimental because they accentuate insulin resistance whereas anticalcineurins, in particular tacrolimus, lower insulin synthesis.
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PMID:Effects of non-steroid immunosuppressive drugs on insulin secretion in transplantation. 1731 44

The immunosuppressant drug FK506 was found to be a potent neuroprotective agent in animal models of brain ischemia. However, the mechanisms underlying the action remain to be elucidated. The delayed rectifier K(+) channel has been implicated in ischemic injury and neuronal death in the brain. The aim of the present study is to investigate whether the neuroprotective action of FK506 results from blocking the K(+) channel. In acutely dissociated CA1 pyramidal neurons of rat hippocampus, superfusion of FK506 (0.01-100 microM) selectively inhibited the delayed rectifier K(+) current (I(K)) with an IC(50) value of 13.2+/-4.9 microM. The inhibition of I(K) by FK506 (10 microM) had a rapid onset, and then gradually reached a steady-state level. The inhibition was voltage-dependent, became more potent when the currents were elicited by strong depolarization. Moreover, FK506 (10 microM) caused marked negative shifts of the steady-state activation and inactivation curves of I(K), and accelerated its recovery from inactivation. Intracellular dialysis of FK506 (30 microM) was ineffective. The inhibition of I(K) by FK506 (10 microM) persisted under the low-Ca(2+) conditions that blocked the basal activity of protein phosphatase 2B (calcineurin). Rapamycin did not antagonize FK506 but mimicked it. Cyclosporin A inhibited I(K) only at 30 and 100 microM. Taken together, the results suggest that FK506 exert a direct inhibition on the delayed rectifier K(+) channel without involvement of calcineurin.
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PMID:Calcineurin-independent inhibition of the delayed rectifier K+ current by the immunosuppressant FK506 in rat hippocampal neurons. 1735 75

The immunosuppressant cyclosporin A (CsA) has been shown to exert potent neuroprotective effects, possibly via the inhibition of calcineurin and mitochondrial permeability transition pore formation. Here, we investigated the neuroprotective profile of a novel derivative of CsA, FR901459, by evaluating its effects against in vitro mitochondrial damage and in vivo brain damage in transient global or focal cerebral ischemia models, in comparison with those of CsA. Efficacy of calcineurin inhibition was estimated from its immunosuppressive effect on the mixed lymphocyte reaction. Results showed that the immunosuppressive effect of FR901459 was approximately 7-fold less potent than that of CsA. In contrast, FR901459 suppressed Ca(2+)-induced mitochondrial swelling measured in isolated liver mitochondria with greater potency than CsA. Further, FR901459 showed approximately 30-fold greater neuroprotective potency than CsA against neuronal cell damage induced by thapsigargin in SH-SY5Y cells. In a transient global cerebral ischemia model in gerbils, FR901459 showed the dose-dependent suppression of neuronal cell death, while FR901459 was less efficacious than CsA. In a rat transient focal ischemia model, FR901459 tended to reduce brain damage on both intravenous injection as well as intracerebroventricular infusion, but with less efficacy than CsA which significantly reduced the damage. These findings suggest that FR901459 exerts a potent neuroprotective effect by inhibiting mitochondrial damage in vitro, but that in in vivo transient cerebral ischemia, its immunosuppressive component which possibly acts via the inhibition of calcineurin may play a more important role in attenuating brain damage than its inhibitory effect against mitochondrial damage.
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PMID:Neuroprotective efficacy of FR901459, a novel derivative of cyclosporin A, in in vitro mitochondrial damage and in vivo transient cerebral ischemia models. 1739 53

We recently demonstrated that a constitutively active form of calcineurin (CaN) is generated by calpain-mediated limited proteolysis following brain ischemia. The calpain-induced CaN activation mediated delayed neuronal death through translocation of nuclear factor of activated T-cells (NFAT) into nuclei after brain ischemia. We also previously demonstrated that activation of forkhead in rhabdomyosarcoma (FKHR), a forkhead transcription factor and substrate of protein kinase-B (Akt), mediated ischemia-induced neuronal death through Fas-ligand expression in gerbil hippocampus. FKHR activation occurred through decreased Akt activity and concomitant dephosphorylation mediated by undefined phosphatases. In this study, we show that phosphorylated Ser-256 of FKHR is dephosphorylated by constitutively active CaN and that in turn FKHR forms a complex with CaN that is translocated into nuclei after brain ischemia. After nuclear translocation of NFAT and FKHR, both NFAT and FKHR stimulated expression of Fas-ligand by binding to its promoter region. Consistent with activation of the Fas-ligand promoter by FKHR dephosphorylation, Fas-ligand expression increased 2 days after ischemia/reperfusion, and treatment with the CaN inhibitor FK506 inhibited that expression. These results suggest that FKHR is a downstream target of CaN and that constitutively active CaN mediates delayed neuronal death through Fas-ligand expression via up-regulation of both NFAT and FKHR transcriptional activity in brain ischemia.
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PMID:Constitutively active calcineurin mediates delayed neuronal death through Fas-ligand expression via activation of NFAT and FKHR transcriptional activities in mouse brain ischemia. 1766 23

Delayed graft function (DGF) in kidney transplantation is associated with an increased risk of acute rejection. Myeloid dendritic cells (DCs) are involved in graft rejection, whereas plasmacytoid DCs may play a role in inducing tolerance. We evaluated the presence and phenotype of the DCs in renal graft biopsies of 15 patients with DGF collected before and 7-15 days after transplantation. Biopsies taken from normal patients and from transplant recipients with acute calcineurin inhibitors (CNIs) nephrotoxicity served as a control group. Specific markers of myeloid, plasmacytoid, and mature DCs were imaged by confocal microscopy and immunohistochemistry. In normal kidneys and pre-transplant biopsies, sparse niches of myeloid and plasmacytoid cells were found but these were significantly increased with few mature cells during DGF. This same pattern was seen in acute rejection but with overall higher cell numbers. In CNI nephrotoxicity, myeloid cells were slightly increased but plasmacytoid cells were significantly higher than in DGF. Using a pig model, we found that a short period of warm ischemia followed by reperfusion led to myeloid cell infiltration of the kidney. Our data suggest that ischemia-reperfusion injury may cause an imbalance between intragraft myeloid and plasmacytoid DCs, which might be related to DGF and acute rejection.
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PMID:Ischemia-reperfusion injury-induced abnormal dendritic cell traffic in the transplanted kidney with delayed graft function. 1768 57

Fibroblast growth factor 2 (FGF-2) plays an integral role in therapeutic angiogenesis associated with myocardial infarct healing. Calcium (Ca(2+)) is one of the most universal important signaling molecules that affect cell proliferation and angiogenesis. Calreticulin (CRT), a 46-kd (Ca(2+)) -binding chaperone found mainly in the endoplasmic reticulum, plays an important role in regulating calcium homeostasis. The role of CRT in FGF-2-induced angiogenesis and its signaling pathways in ischemic myocardium are not clear. For this study, two-dimensional gel electrophoresis and matrix-assisted laser desorption ionization mass spectrometry were used to analyze CRT's differential expression in myocardial microvascular endothelial cells treated with or without FGF-2. Western blotting analysis was used to detect the expression of CRT and calcineurin (CaN) in sham-operated, FGF-2-, or saline intramyocardially injected myocardium. It is found that FGF-2 induced angiogenesis after sustained ischemia with downregulation of CRT expression and upregulation of CaN expression in myocardium. The CRT expression was negatively correlated to angiogenesis. Furthermore, overexpression of CRT or inhibition of CaN with cyclosporine A abolishes FGF-2-induced microvascular endothelial cells proliferation and CaN expression. The results indicate that intramyocardial administration of FGF-2 decreases myocardial CRT expression in parallel with myocardial angiogenesis in ischemic myocardium. The study further indicates that Ca(2+)/CaN signaling pathway may be involved in CRT-related angiogenesis.
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PMID:Calreticulin downregulation is associated with FGF-2-induced angiogenesis through calcineurin pathway in ischemic myocardium. 1769 30

Cytosolic calcium-dependent phospholipase A(2) (cPLA(2)) has multiple roles including production of arachidonic acid (a key player in cellular signaling pathways) and membrane remodeling. Additionally, since catabolism of arachidonic acid generates free radicals, the enzyme is also implicated in ischemic injury to mammalian organs. Regulation of cPLA(2) could be important in the suppression and prioritization of cellular pathways in animals that undergo reversible transitions into hypometabolic states. The present study examines the responses and regulation of cPLA(2) in skeletal muscle and liver of hibernating thirteen-lined ground squirrels, Spermophilus tridecemlineatus. cPLA(2) activity decreased significantly by 43% in liver during hibernation, compared with euthermic controls, and K(m) values for arachidonoyl thio-PC substrate fell in both organs during hibernation to 61% in liver and 28% in muscle of the corresponding euthermic value. To determine whether these responses were due to a change in the phosphorylation state of the enzyme, Western blotting was employed using antibodies recognizing phospho-Ser(505) on alpha-cPLA(2). The amount of phosphorylated alpha-cPLA(2) in hibernator liver was just 38% of the value in euthermic liver. Furthermore, incubation of liver extracts under conditions that enhanced protein phosphatase action caused a greater reduction in the detectable amount of phospho-Ser(505) enzyme content in euthermic, versus hibernator, extracts. The data are consistent with a suppression of cPLA(2) function during torpor via enzyme dephosphorylation, an action that may contribute to the well-developed ischemia tolerance and lack of oxidative damage found in hibernating species over cycles of torpor and arousal.
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PMID:Cytosolic phospholipase A2 regulation in the hibernating thirteen-lined ground squirrel. 1772 82


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