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: UNIPROT:P10415 (Bcl-2)
33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Delayed cardio- and neuroprotection are observed following a preconditioning procedure evoked by a brief and nontoxic oxidative stress due to deprivation of oxygen, glucose, serum, trophic factors, and/or antioxidative enzymes. Preconditioning protection can be observed in vivo and is under clinical trials for preservation of cell viability following organ transplants of liver. Previous studies indicated that ischemic preconditioning increases the expression of heat-shock proteins (HSPs) and nitric oxide synthase (NOS). Our pilot studies indicate that the treatment of neuronal NOS inhibitor (7-nitroindazole) and 6Br-cGMP blocks and mimics, respectively, preconditioning protection in human neuroblastoma SH-SY5Y cells. This minireview focuses on nitric oxide-mediated cellular adaptation and the related cGMP/PKG signaling pathway in a compensatory mechanism underlying preconditioning-induced hormesis. Both preconditioning and 6Br-cGMP increase the induction of human thioredoxin (Trx) mRNA and protein for cytoprotection, which is largely prevented by transfection of cells with Trx antisense but not sense oligonucleotides. Cytosolic Trx1 and mitochondrial Trx2 suppress free radical formation, lipid peroxidation, oxidative stress, and mitochondria-dependent apoptosis; knock out/down of either Trx1 or Trx2 is detrimental to cell survival. Other recent findings indicate that a transgenic increase of Trx in mice increases tolerance against oxidative nigral injury caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Trx1 can be translocated into nucleus and phosphoactivated CREB for a delayed induction of mitochondrial anti-apoptotic Bcl-2 and antioxidative MnSOD that is known to increase vitality and survival of cells in the brain and the heart. In conclusion, preconditioning adaptation or a brief oxidative stress induces a delayed nitric oxide-mediated compensatory mechanism for cell survival and vitality in the central nervous system and the cardiovascular system. Preconditioning-induced adaptive tolerance may be signaling through a cGMP-dependent induction of cytosolic redox protein Trx1 and subsequently mitochondrial proteins such as Bcl-2, MnSOD, and perhaps Trx2 or HSP70.
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PMID:Induction of thioredoxin and mitochondrial survival proteins mediates preconditioning-induced cardioprotection and neuroprotection. 1596 87

Oxidative stress and apoptosis may play an important role in the neurodegeneration. The present paper outlines antioxidative and antiapototic mechanisms of nitric oxide and S-nitrosothiols, which could mediate neuroprotection. Nitric oxide generated by nitric oxide synthase or released from an endogenous S-nitrosothiol, S-nitrosoglutathione may up-regulate antioxidative thioredoxin system and antiapototic Bcl-2 protein through a cGMP-dependent mechanism. Moreover, nitric oxide radicals have been shown to have direct antioxidant effect through their reaction with free radicals and iron-oxygen complexes. In addition to serving as a stabilizer and carrier of nitric oxide, S-nitrosoglutathione may have protective effect through transnitrosylation reactions. Based on these new findings, a hypothesis arises that the homeostasis of nitric oxide, S-nitrosothiols, glutathione, and thioredoxin systems is important for protection against oxidative stress, apoptosis, and related neurodegenerative disorders.
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PMID:Neuroprotective properties of nitric oxide and S-nitrosoglutathione. 1598 48

Hormesis, a stress tolerance, can be induced by ischemic preconditioning stress. In addition to preconditioning, it may be induced by other means, such as gas anesthetics. Preconditioning mechanisms, which may be mediated by reprogramming survival genes and proteins, are obscure. A known neurotoxicant, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), causes less neurotoxicity in the mice that are preconditioned. Pharmacological evidences suggest that the signaling pathway of NO-cGMP-PKG (protein kinase G) may mediate preconditioning phenomenon. We developed a human SH-SY5Y cell model for investigating ()NO-mediated signaling pathway, gene regulation, and protein expression following a sublethal preconditioning stress caused by a brief 2-h serum deprivation. Preconditioned human SH-SY5Y cells are more resistant against severe oxidative stress and apoptosis caused by lethal serum deprivation and 1-methyl-4-phenylpyridinium (MPP(+)). Both sublethal and lethal oxidative stress caused by serum withdrawal increased neuronal nitric oxide synthase (nNOS/NOS1) expression and ()NO levels to a similar extent. In addition to free radical scavengers, inhibition of nNOS, guanylyl cyclase, and PKG blocks hormesis induced by preconditioning. S-nitrosothiols and 6-Br-cGMP produce a cytoprotection mimicking the action of preconditioning tolerance. There are two distinct cGMP-mediated survival pathways: (i) the up-regulation of a redox protein thioredoxin (Trx) for elevating mitochondrial levels of antioxidant protein Mn superoxide dismutase (MnSOD) and antiapoptotic protein Bcl-2, and (ii) the activation of mitochondrial ATP-sensitive potassium channels [K(ATP)]. Preconditioning induction of Trx increased tolerance against MPP(+), which was blocked by Trx mRNA antisense oligonucleotide and Trx reductase inhibitor. It is concluded that Trx plays a pivotal role in ()NO-dependent preconditioning hormesis against MPTP/MPP(+).
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PMID:Roles of thioredoxin in nitric oxide-dependent preconditioning-induced tolerance against MPTP neurotoxin. 1600 85

Nicorandil has been shown to inhibit myocyte apoptosis by opening of mitochondrial ATP-sensitive potassium (mitoK(ATP)) channels and nitrate-like effect against oxidative stress. However, the detailed mechanism of nicorandil-mediated cardioprotection under hypoxic conditions remains to be largely unknown. The present study examined whether nicorandil can inhibit apoptosis via regulation of Bcl-2 family proteins in hypoxic myocytes. Neonatal rat cardiac myocytes were exposed to hypoxia for 7 hours. Hypoxia-induced myocyte apoptosis (13.9+/-0.9%) under glucose-rich conditions. Myocyte apoptosis was accompanied by loss of mitochondrial membrane potential (Deltapsi(m)), cytochrome c release from mitochondria into cytosol, and activation of caspase-3. Hypoxia also significantly increased Bax and decreased Bcl-2 mRNA and protein expression, thereby increasing Bax/Bcl-2 ratio. Nicorandil 100 micromol/l significantly decreased the percentage of apoptotic myocytes (7.2+/-0.5%) by inhibiting loss of Deltapsi(m) and translocation of cytochrome c. These effects of nicorandil were partially but significantly inhibited by cotreatment of either 500 micromol/l 5-hydroxydecanoate, a selective mitoK(ATP) channel antagonist, or 10 micromol/l 1H-[1,2,4]oxidazolo[4,3-a]quinoxalin-1-one (ODQ), an inhibitor of soluble guanylate cyclase. Moreover, nicorandil significantly inhibited the hypoxia-induced changes in Bax and Bcl-2 expression, and concomitant increased Bax and decreased Bcl-2 immunoreactivity in mitochondria. These effects of nicorandil in Bax and Bcl-2 expression were significantly blunted by cotreatment of ODQ and 5-HD, respectively. Cotreatment of KT5823, an inhibitor of protein kinase G, significantly blocked the effect of nicorandil on Bax expression and 8-bromo-cyclic guanosine 3',5' monophosphate (8-bromo-cGMP), a cGMP analog, mimicked the effect of nicorandil on Bax expression. The present study demonstrates that nicorandil regulates Bcl-2 family proteins via opening of mitoK(ATP) channels and nitric oxide-cGMP signaling and inhibits hypoxia-induced mitochondrial death pathway.
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PMID:Nicorandil regulates Bcl-2 family proteins and protects cardiac myocytes against hypoxia-induced apoptosis. 1652 5

Cyclic GMP-dependent protein kinases protein kinase G (PKG) Ialpha and PKGIbeta are major mediators of cGMP signaling in the cardiovascular system. PKGIalpha is present in the heart, although its role in protection against ischemia/reperfusion injury is not known. We investigated the direct effect of PKGIalpha against necrosis and apoptosis following simulated ischemia (SI) and reoxygenation (RO) in cardiomyocytes. Adult rat cardiomyocytes were infected with adenoviral vectors containing hPKGIalpha or catalytically inactive mutant hPKGIalphaK390A. After 24 h, the cells were subjected to 90 min of SI and 2 h RO for necrosis (trypan blue exclusion and lactate dehydrogenase release) or 18 h RO for apoptosis studies. To evaluate the role of K(ATP) channels, subgroups of cells were treated with 5-hydroxydecanoate (100 microm), HMR1098 (30 microm), or glibenclamide (50 microm), the respective blockers of mitochondrial, sarcolemmal, or both types of K(ATP) channels prior to SI. The necrosis observed in 33.7 +/- 1.6% of total myocytes in the SI-RO control group was reduced to 18.6 +/- 0.8% by PKGIalpha (mean +/- S.E., n = 7, p < 0.001). The apoptosis observed in 17.9 +/- 1.3% of total myocytes in the SI-RO control group was reduced to 6.0 +/- 0.6% by PKGIalpha (mean +/- S.E., n = 7, p < 0.001). In addition, PKGIalpha inhibited the activation of caspase-3 after SI-RO in myocytes. Myocytes infected with the inactive PKGIalphaK390A mutant showed no protection. PKGIalpha enhanced phosphorylation of Akt, ERK1/2, and JNK, increased Bcl-2, inducible nitric-oxide synthase, endothelial nitric-oxide synthase, and decreased Bax expression. 5-Hydroxydecanoate and glibenclamide abolished PKGIalpha-mediated protection against necrosis and apoptosis. However, HMR1098, had no effect. A scavenger of reactive oxygen species, as well as inhibitors of phosphatidylinositol 3-kinase, ERK, JNK1, and NOS, also blocked PKGIalpha-mediated protection against necrosis and apoptosis. These results show that opening of mitochondrial K(ATP) channels and generation of reactive oxygen species, in association with phosphorylation of Akt, ERK, and JNK, and increased expression of NOS and Bcl-2, play an essential role in the protective effect of PKGIalpha.
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PMID:Cyclic GMP-dependent protein kinase Ialpha attenuates necrosis and apoptosis following ischemia/reoxygenation in adult cardiomyocyte. 1703 26

Growing evidence suggests that multiple spatially, temporally, and functionally distinct pools of cyclic nucleotides exist and regulate cardiac performance, from acute myocardial contractility to chronic gene expression and cardiac structural remodeling. Cyclic nucleotide phosphodiesterases (PDEs), by hydrolyzing cAMP and cyclic GMP, regulate the amplitude, duration, and compartmentation of cyclic nucleotide-mediated signaling. In particular, PDE3 enzymes play a major role in regulating cAMP metabolism in the cardiovascular system. PDE3 inhibitors, by raising cAMP content, have acute inotropic and vasodilatory effects in treating congestive heart failure but have increased mortality in long-term therapy. PDE3A expression is downregulated in human and animal failing hearts. In vitro, inhibition of PDE3A function is associated with myocyte apoptosis through sustained induction of a transcriptional repressor ICER (inducible cAMP early repressor) and thereby inhibition of antiapoptotic molecule Bcl-2 expression. Sustained induction of ICER may also cause the change of other protein expression implicated in human and animal failing hearts. These data suggest that the downregulation of PDE3A observed in failing hearts may play a causative role in the progression of heart failure, in part, by inducing ICER and promoting cardiac myocyte dysfunction. Hence, strategies that maintain PDE3A function may represent an attractive approach to circumvent myocyte apoptosis and cardiac dysfunction.
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PMID:Regulation of phosphodiesterase 3 and inducible cAMP early repressor in the heart. 1733 39

In the case of left ventricle remodeling after myocardial infarction, cardiomyocyte apoptosis is attributed to increased cardiac workload by the stimulus such as chronic hypoxia. B-Type natriuretic peptide, being known as a reliable prognostic of cardiovascular pathology, plays an important role in the myocardial infarction. However, the action of B-type natriuretic peptide on cardiomyocytes undergoing apoptosis is unclear. In the present study, B-type natriuretic peptide have exhibited the enhancive effects on the mild hypoxia-induced cardiomyocyte apoptosis with the manifestation of facilitating phosphatidylserine evagination and increasing typical fragmented nuclei. In addition, B-type natriuretic peptide aggravated the dissipation of delta psi(m), the depletion of intracellular ATP and the increase of caspase-3 activity. 8-Bromo-cGMP, which increased cGMP independent of B-type natriuretic peptide, could mimic B-type natriuretic peptide's effects; whereas cGMP-dependent protein kinase inhibitor, Rp-8-br-cGMP inhibited that. Further study revealed the enhancive effect of BNP on down-regulation of Bcl-2 mRNA expression in the presence of mild hypoxia. In conclusion, the present study demonstrated that B-type natriuretic peptide aggravated the cardiomyocyte apoptosis by influencing hypoxia-induced mitochondrial death pathway, which is true at least in this oxygen deprivation model; and this effect was partially realized through intracellular cGMP.
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PMID:B-type natriuretic peptide enhances mild hypoxia-induced apoptotic cell death in cardiomyocytes. 1754 Nov 58

We have characterized lipopolysaccharide (LPS) preconditioning-induced neuroprotective mechanisms against nitric oxide (NO) toxicity. Pretreatment of rat cortical cultures with LPS attenuated neurotoxicity of NO donors, including sodium nitroprusside (SNP) and diethylamine NONOate (NONOate). A transiently increased expression of endothelial nitric oxide synthase (eNOS) accompanied by an increase in NO production was observed during LPS preconditioning. Application of NOS inhibitors including L-N(5)-(1-iminoethyl)-ornithine (L-NIO) and L-nitroarginine methylester (L-NAME) abolished LPS-dependent protection against SNP toxicity. The LPS effect was also blocked by KT5823, an inhibitor of cGMP-dependent protein kinase (PKG). Consistently, application of 8-bromo-cyclic GMP (8-Br-cGMP), a slowly degradable cGMP analogue capable of PKG activation, was neuroprotective. LPS preconditioning resulted in a heightened neuronal expression of Bcl-2 protein that was abolished by L-NAME and KT5823, the respective inhibitors of NOS and PKG. Together, our results reveal the signaling cascade of "LPS --> eNOS --> NO --> cGMP/PKG --> Bcl-2" that might have contributed to the LPS protective effects in cortical neurons.
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PMID:Protective effects of lipopolysaccharide preconditioning against nitric oxide neurotoxicity. 1809 58

Sildenafil, a potent inhibitor of phosphodiesterase-5 (PDE-5) induces powerful protection against myocardial ischemia-reperfusion injury. PDE-5 inhibition increases cGMP levels that activate cGMP-dependent protein kinase (PKG). However, the cause and effect relationship of PKG in sildenafil-induced cardioprotection and the downstream targets of PKG remain unclear. Adult ventricular myocytes were treated with sildenafil and subjected to simulated ischemia and reoxygenation. Sildenafil treatment significantly decreased cardiomyocyte necrosis and apoptosis. The PKG inhibitors, KT5823, guanosine 3',5'-cyclic monophosphorothioate, 8-(4-chloro-phenylthio) (R(p)-8-pCPT-cGMPs), or DT-2 blocked the anti-necrotic and anti-apoptotic effect of sildenafil. Selective knockdown of PKG in cardiomyocytes with adenoviral vector containing short hairpin RNA of PKG also abolished sildenafil-induced protection. Furthermore, intra-coronary infusion of sildenafil in Langendorff-isolated mouse hearts prior to ischemia-reperfusion significantly reduced myocardial infarct size after 20 min ischemia and 30 min reperfusion, which was abrogated by KT5823. Sildenafil significantly increased PKG activity in intact hearts and cardiomyocytes. Sildenafil also enhanced the Bcl-2/Bax ratio, phosphorylation of Akt, ERK1/2, and glycogen synthase kinase 3beta. All these changes (except Akt phosphorylation) were significantly blocked by KT5823 and short hairpin RNA of PKG. These studies provide the first evidence for an essential role of PKG in sildenafil-induced cardioprotection. Moreover, our results demonstrate that sildenafil activates a PKG-dependent novel signaling cascade that involves activation of ERK and inhibition of glycogen synthase kinase 3beta leading to cytoprotection.
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PMID:Protein kinase G-dependent cardioprotective mechanism of phosphodiesterase-5 inhibition involves phosphorylation of ERK and GSK3beta. 1872 5

Astrocytes, the most abundant glial cell type in the brain, provide metabolic and trophic support to neurons and modulate synaptic activity. In response to a brain injury, astrocytes proliferate and become hypertrophic with an increased expression of intermediate filament proteins. This process is collectively referred to as reactive astrocytosis. Lipocalin 2 (lcn2) is a member of the lipocalin family that binds to small hydrophobic molecules. We propose that lcn2 is an autocrine mediator of reactive astrocytosis based on the multiple roles of lcn2 in the regulation of cell death, morphology, and migration of astrocytes. lcn2 expression and secretion increased after inflammatory stimulation in cultured astrocytes. Forced expression of lcn2 or treatment with LCN2 protein increased the sensitivity of astrocytes to cytotoxic stimuli. Iron and BIM (Bcl-2-interacting mediator of cell death) proteins were involved in the cytotoxic sensitization process. LCN2 protein induced upregulation of glial fibrillary acidic protein (GFAP), cell migration, and morphological changes similar to characteristic phenotypic changes termed reactive astrocytosis. The lcn2-induced phenotypic changes of astrocytes occurred through a Rho-ROCK (Rho kinase)-GFAP pathway, which was positively regulated by nitric oxide and cGMP. In zebrafishes, forced expression of rat lcn2 gene increased the number and thickness of cellular processes in GFAP-expressing radial glia cells, suggesting that lcn2 expression in glia cells plays an important role in vivo. Our results suggest that lcn2 acts in an autocrine manner to induce cell death sensitization and morphological changes in astrocytes under inflammatory conditions and that these phenotypic changes may be the basis of reactive astrocytosis in vivo.
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PMID:Lipocalin-2 is an autocrine mediator of reactive astrocytosis. 1912


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