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)

Calpain, a Ca(2+)-dependent cysteine protease, in vitro converts calcineurin (CaN) to constitutively active forms of 45 kDa and 48 kDa by cleaving the autoinhibitory domain of the 60 kDa subunit. In a mouse middle cerebral artery occlusion (MCAO) model, calpain converted the CaN A subunit to the constitutively active form with 48 kDa in vivo. We also confirmed increased Ca(2+)/CaM-independent CaN activity in brain extracts. The generation of constitutively active and Ca(2+)/CaM-independent activity of CaN peaked 2 h after reperfusion in brain extracts. Increased constitutively active CaN activity was associated with dephosphorylation of dopamine-regulated phosphoprotein-32 in the brain. Generation of constitutively active CaN was accompanied by translocation of nuclear factor of activated T-cells (NFAT) into nuclei of hippocampal CA1 pyramidal neurons. In addition, a novel calmodulin antagonist, DY-9760e, blocked the generation of constitutively active CaN by calpain, thereby inhibiting NFAT nuclear translocation. Together with previous studies indicating that NFAT plays a critical role in apoptosis, we propose that calpain-induced CaN activation in part mediates delayed neuronal death in brain ischemia.
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PMID:Generation of constitutively active calcineurin by calpain contributes to delayed neuronal death following mouse brain ischemia. 1680 17

Transient cerebral ischemia causes an inhomogeneous pattern of cell death in the brain. We investigated mechanisms, which may underlie the greater susceptibility of hippocampal CA1 vs. CA3 pyramidal cells to ischemic insult. Using an in vitro oxygen-glucose deprivation (OGD) model of ischemia, we found that N-methyl-D-aspartate (NMDA) responses were enhanced in the more susceptible CA1 pyramidal cells and transiently depressed in the resistant CA3 pyramidal cells. The long-lasting potentiation of NMDA responses in CA1 cells was associated with delayed cell death and was prevented by blocking tyrosine kinase-dependent up-regulation of NMDA receptor function. In CA3 cells, the energy deprivation-induced transient depression of NMDA responses was converted to potentiation by blocking protein phosphatase signalling. These results suggest that energy deprivation differentially shifts the intracellular equilibrium between the tyrosine kinase and phosphatase activities that modulate NMDA responses in CA1 and CA3 pyramidal cells. Therapeutic modulation of tyrosine phosphorylation may thus prove beneficial in mitigating ischemia-induced neuronal death in vulnerable brain areas.
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PMID:NMDA receptors and the differential ischemic vulnerability of hippocampal neurons. 1681 62

Lithium used in bipolar mood disorder therapy protects neurons from brain ischemic cell death. Here, we documented that lithium administration under microsphere-embolism (ME)-induced brain ischemia restored decreased protein kinase B (Akt) and Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) activities 24 h after ischemia in rat brain. Akt activation was associated with increased phosphorylation of its potential targets forkhead transcription factor (FKHR) and glycogen synthase kinase-3beta (GSK-3beta). In parallel with decreased CaMKII autophosphorylation, we also found marked dephosphorylation of tau proteins 24-72 h after ME. Increased protein phosphatase 2A (PP2A) activity was found 24 h after ME. Inhibition of increased PP2A activity by lithium treatment apparently mediated restored tau phosphorylation. Taken together, activation of Akt and CaMKII by lithium was associated with neuroprotective activity in ME-induced neuronal injury.
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PMID:Lithium-induced activation of Akt and CaM kinase II contributes to its neuroprotective action in a rat microsphere embolism model. 1684 47

Estrogen exerts complex biological effects through the two isoforms of estrogen receptors (ERs): ERalpha and ERbeta. Whether through alteration of gene expression or rapid, plasma membrane-localized signaling to non-transcriptional actions, estrogen-activated ERs have significant implications in cardiovascular physiology. 17-beta-estradiol (E2) generally has a protective property on the vasculature. Estrogen treatment is anti-atherogenic, protecting injured endothelial surfaces and lowering LDL oxidation in animal models. Increased NO production stimulated by E2 results in vasodilation of the coronary vascular bed, and involves rapid activation of phosphotidylinositol-3 kinase (PI3K)/Akt signaling to eNOS in carotid and femoral arteries. Both isoforms of ERs impact various vascular functions, modulating ion channel integrity, mitigating the response to arterial injury, inducing vasodilation, and preventing development of hypertension in animal models. In addition to reducing afterload by vasodilation, ERs have a direct antihypertrophic effect on the myocardium. E2-activated ERs (E2/ER) antagonize the hypertrophic pathway induced by vasoactive peptides such as angiotensin II by activating PI3K, subsequent MICIP gene expression, leading to the inhibition of calcineurin activity and the induction of hypertrophic genes. In models of ischemia-reperfusion, E2/ER is antiapoptotic for cardiomyocytes, exerting the protective actions via PI3K and p38 MAP kinases and suppressing the generation of reactive oxygen species. In sum, E2-activated ERs consistently and positively modulate multiple aspects of the cardiovascular system.
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PMID:Estrogen signaling in the cardiovascular system. 1686 19

Sirolimus, a macrocylic lactone, blocks T-cell activation by a mechanism of action distinct from calcineurin inhibitors (CNIs). Therefore, it may be expected that sirolimus would display a safety profile without the vasomotor form of nephrotoxicity characteristic of CNIs. Initial studies in rodent models and in psoriasis patients showed that sirolimus alone did not impair renal function. Subsequently, two pivotal, randomized double dummy, phase III trials in human renal transplantation demonstrated that sirolimus exacerbated the nephrotoxicity of full doses of CNIs. Both pharmacokinetic and pharmacodynamic mechanisms have been implicated in the pathogenesis of this disorder. Subsequent experience has shown that cyclosporin A dose reduction, elimination, or avoidance mitigates these effects, particularly in patients distant from the transplant procedure. However, there is concern about recovery from ischemia-reperfusion injury. Animal models suggesting that sirolimus may delay recovery in this setting have been supported by non-randomized experiences at single centers, which have observed an increased incidence of delayed graft function among sirolimus-treated recipients. In contrast, large single- and multi-center studies have not confirmed this finding; impaired renal recovery has been observed in only occasional instances. Thus, present data indicate that sirolimus does not impair the function of an uninjured kidney, but whether the drug acts alone or potentiates conditions that delay recovery after ischemic injury remains to be established by large randomized trials specifically targeted to recipients at high risk for this complication.
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PMID:The place of sirolimus in kidney transplantation: can we reduce calcineurin inhibitor renal toxicity? 1687 Dec 48

Increased levels of protein O-linked N-acetylglucosamine (O-GlcNAc) have been shown to increase cell survival following stress. Therefore, the goal of this study was to determine whether in isolated neonatal rat ventricular myocytes (NRVMs) an increase in protein O-GlcNAcylation resulted in improved survival and viability following ischemia-reperfusion (I/R). NRVMs were exposed to 4 h of ischemia and 16 h of reperfusion, and cell viability, necrosis, apoptosis, and O-GlcNAc levels were assessed. Treatment of cells with glucosamine, hyperglycemia, or O-(2-acetamido-2-deoxy-D-glucopyranosylidene)-amino-N-phenylcarbamate(PUGNAc), an inhibitor of O-GlcNAcase, significantly increased O-GlcNAc levels and improved cell viability, as well as reducing both necrosis and apoptosis compared with untreated cells following I/R. Alloxan, an inhibitor of O-GlcNAc transferase, markedly reduced O-GlcNAc levels and exacerbated I/R injury. The improved survival with hyperglycemia was attenuated by azaserine, which inhibits glucose metabolism via the hexosamine biosynthesis pathway. Reperfusion in the absence of glucose reduced O-GlcNAc levels on reperfusion compared with normal glucose conditions and decreased cell viability. O-GlcNAc levels significantly correlated with cell viability during reperfusion. The effects of glucosamine and PUGNAc on cellular viability were associated with reduced calcineurin activation as measured by translocation of nuclear factor of activated T cells, suggesting that increased O-GlcNAc levels may attenuate I/R induced increase in cytosolic Ca(2+). These data support the concept that activation of metabolic pathways leading to an increase in O-GlcNAc levels is an endogenous stress-activated response and that augmentation of this response improves cell survival. Thus strategies designed to activate these pathways may represent novel interventions for inducing cardioprotection.
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PMID:Glucosamine protects neonatal cardiomyocytes from ischemia-reperfusion injury via increased protein-associated O-GlcNAc. 1689 50

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

In the present study, we investigated whether the protective effect of FK506 and cyclosporin A (CsA) against in vitro ischemic injury of astrocytes might be mediated through attenuation of cytosolic isoform of phospholipase A(2) (cPLA(2)) expression and activity as well as inhibition of arachidonic acid (AA) release. On the 21st day in vitro, cultures of rat astrocytes were subjected to ischemia-simulating conditions (combined oxygen glucose deprivation) for 8 h and exposed to FK506 (10 - 1,000 nM) and CsA (0.25 - 10 microM). Obtained data suggest the cross-talk between the action of 0.25 - 10 microM CsA as well as 1 microM FK506 on calcineurin (CaN) and cPLA(2) in anti-apoptotic signal transduction pathways. Moreover, we have shown that immunosuppressants at these concentrations protected glial cells against ischemia-induced apoptosis through the increase of cell viability, mitochondrial function restoration, and attenuation of oxidative stress. Finally, in our study, low concentrations of FK506 (10 and 100 nM) exerted limited effects on the assessed parameters. Our findings document a key role either for CaN or cPLA(2) expression attenuation and AA release inhibition in the antiapoptotic effect of FK506 and CsA in ischemic astrocytes.
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PMID:Inhibition of arachidonic acid release by cytosolic phospholipase A2 is involved in the antiapoptotic effect of FK506 and cyclosporin a on astrocytes exposed to simulated ischemia in vitro. 2908 42

The present study focused on mechanisms involved in the anti-apoptotic effect of cyclosporin A (CsA) towards ischemic injured astrocytes in vitro [under combined oxygen glucose deprivation (OGD)]. We investigated whether this action might be mediated through activation of extracellular signal regulated kinases 1 and 2 (Erk1/2) or attenuation of calcineurin (CaN) by immunosuppressant in ischemic astrocytes. Additionally, the influence of CsA on phosphorylation of Akt kinase was determined. After 21 days of in vitro culture, astrocytes were subjected to OGD (for 8 h) and CsA (0.25-10 microM); 0.25 microM CsA distinctly stimulated the Erk1/2 pathway in astrocytes exposed to OGD. This protective effect of CsA was strongly associated with CaN inhibition, increased expression of anti-apoptotic factors such as Bcl-X(L) and NF-kappaB, as well as suppression of caspase-3 activity. Maximum p-Akt kinase expression was observed following treatment with 1 microM CsA. Finally, we also demonstrated that the beneficial effect of CsA at a concentration of 10 microM is related mainly to strong CaN inhibition. The results obtained suggest that, depending on the concentration used, CsA might act as a protective agent towards ischemia-injured astroglial cells through alternative intracellular pathways associated with increased p-Erk1/2 and p-Akt expression or CaN inactivation.
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PMID:Calcineurin and Erk1/2-signaling pathways are involved in the antiapoptotic effect of cyclosporin A on astrocytes exposed to simulated ischemia in vitro. 1702 52

Chronic Allograft Nephropathy (CAN) is one of the most common cause of kidney transplant loss. CAN may be caused by immunologic as well as nonimmunologic factors which may interfere and increase response. Immunologic factors include acute rejection, degree of HLA mismatch, inadequate immunosuppression. Nonimmunologic factors contain delayed graft function, ischemia-reperfusion injury, nephrotoxicity of calcineurin inhibitors, hyperfiltration, hypertension and hyperlipidemia. The histopatological description of CAN may indicate two phases of injury. An initial phase by one year include tubulointerstitial infiltration in the late phase of CAN arteriolar hyalinosis and glomerulosclerosis were revealed. Modification of the immunosuppressive treatment with reduction or withdrawal of calcineurin inhibitors may prevent graft loss, while addition of nonnephrotoxic agents such as mycophenolate mofetil or sirolimus should be considered by the risk of acute rejection. Additionally effective management by hypertension and hyperlipidemia is essential.
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PMID:Chronic allograft nephropathy--immunologic and nonimmunologic factors. 1702 23


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