Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An ERK MAP kinase-mediated contractile mechanism previously reported to be activated by peroxide and stretch in bovine coronary arteries is shown in this study to be present in endothelium-denuded bovine pulmonary arteries and subject to regulation by modulation of cytosolic NAD(H) redox through the lactate dehydrogenase reaction. Although our previous work identified an acute PO2-dependent peroxide-mediated relaxation of bovine pulmonary arteries on exposure to lactate, a 30-min treatment with 10 mM lactate enhanced ERK phosphorylation and increased force generation to 30 mM KCl. Hypoxia inhibited these responses to lactate. Increases in ERK phosphorylation and the enhancement of force generation by lactate and stretch are attenuated in the presence of inhibitors of Nox oxidase (0.1 mM apocynin) or ERK activation (10 microM PD-98059) and by 0.1 mM ebselen. Additionally, incubation of pulmonary arteries with 10 mM pyruvate lowered basal levels of ERK phosphorylation, and it inhibited both the ERK phosphorylation and the enhancement in force generation to 30 mM KCl caused by stretch. Treatment of pulmonary arteries with the thiol oxidant diamide (1 microM) elicited what appears to be a peroxide-independent increase in force and ERK phosphorylation that were both attenuated by PD-98059. Thus pulmonary arteries possess a peroxide-elicited contractile mechanism involving ERK MAP kinase, which is stimulated by stretch and regulated through the control of Nox oxidase activity by the availability of cytosolic NADH.
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PMID:Cytosolic NADH redox and thiol oxidation regulate pulmonary arterial force through ERK MAP kinase. 1566 44

Nitric oxide (NO) has been shown to play a key role in the regulation of cardiac hypertrophy and fibrosis in response to myocardial ischemia in part by antagonizing the action of angiotensin II (Ang II). In this study, we investigated the potential protective role of human endothelial nitric oxide synthase (eNOS) in left ventricular (LV) remodeling after myocardial infarction (MI) by a somatic gene transfer approach. Male Wistar rats underwent coronary artery ligation to induce MI. One week after surgery, adenovirus encoding the human eNOS or luciferase gene under the control of the CMV promoter/enhancer was injected into rats via the tail vein, and animals were sacrificed at 1 and 5 weeks after gene transfer. Successful gene transfer was evaluated based on increased levels of NO and cGMP in the heart, measured at one week after eNOS gene delivery. Six weeks after MI, the LV end-diastolic pressure, heart weight, LV axis length and cardiomyocyte size were markedly increased compared to the Sham group, while eNOS gene delivery significantly reduced these parameters. Rats receiving control virus developed considerably more fibrotic lesions identified by Sirius Red staining and collagen I immunostaining compared to Sham rats, and eNOS gene delivery significantly reduced collagen accumulation. eNOS gene transfer also reduced TUNEL-positive apoptotic cells. The cardioprotective effect of NO was accompanied by reduced NADH and NADPH oxidase activities and superoxide formation, TGF-beta1 and p27 levels, JNK activation, NF-kappa B nuclear translocation, and caspase-3 activity. This study shows that NO may play an important role in attenuating cardiac remodeling and apoptosis after myocardial infarction via suppression of oxidative stress-mediated signaling pathways.
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PMID:Human endothelial nitric oxide synthase gene delivery protects against cardiac remodeling and reduces oxidative stress after myocardial infarction. 1576 77

Glucose transport is stimulated in a variety of cells and tissues in response to inhibition of oxidative phosphorylation. However, the underlying mechanisms and mediating steps remain largely unknown. In the present study we first tested whether a decrease in the redox state of the cell per se and the resultant increase in generation of reactive oxygen species (ROS) lead to stimulation of glucose transport. Clone 9 cells (expressing the Glut1 isoform of facilitative glucose transporters) were exposed to azide, lactate, and ethanol for 1 h. Although all three agents stimulated glucose transport and increased cell NADH-to-NAD(+) ratio and phospho-ERK1/2, signifying increased ROS generation, the response to the stimuli was not blocked by N-acetyl-l-cysteine (an agent that counteracts ROS); moreover, the response to azide was not blocked by diamide (an intracellular sulfhydryl oxidizing agent). We then found that cell AMP-to-ATP and ADP-to-ATP ratios were increased and 5'-AMP-activated protein kinase (AMPK) was stimulated by all three agents, as evidenced by increased phosphorylation of AMPK and acetyl-CoA carboxylase. We conclude that although azide, lactate, and ethanol increase NADH-to-NAD(+) ratios and ROS production, their stimulatory effect on glucose transport is not mediated by increased ROS generation. However, all three agents increased cell AMP-to-ATP ratio and stimulated AMPK, making it likely that the latter pathway plays an important role in the glucose transport response.
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PMID:Role of 5'-AMP-activated protein kinase in stimulation of glucose transport in response to inhibition of oxidative phosphorylation. 1616 57

Pro-inflammatory cytokines have been shown to depress myocardial mechanical function by enhancing peroxynitrite generation in the heart. The contribution of NO synthesized by different NOS isoforms, as well as the contribution of superoxide to this mechanism are still not clear. Isolated working hearts of iNOS(-/-) and wildtype mice were perfused for 120 min in the presence or absence of a mixture of pro-inflammatory cytokines (IL-1beta, TNF-alpha, and IFN-gamma). iNOS mRNA was detected only in cytokine-treated wildtype hearts. In wildtype hearts, cytokine treatment significantly decreased cardiac work, calculated as cardiac output times peak systolic pressure, to 31+/-9% of original values by the end of perfusion (P <0.05). The decline of cardiac work induced by cytokine treatment was significantly reduced in iNOS(-/-) hearts (63+/-5% of original value). Only cytokine-treated wildtype hearts showed decreased aconitase activity, indicating a higher level of oxidative stress in these hearts. Cytokines increased NADPH oxidase activity in both wildtype and iNOS(-/-) hearts, whereas NADH oxidase and xanthine oxidase/xanthine dehydrogenase activities were unaffected. The SOD mimetic MnTE2PyP prevented the cytokine-induced decline of cardiac work in both wildtype and iNOS(-/-) hearts. Cardiac p38 MAPK activation was unaltered in all experimental groups. Although genetic disruption of the iNOS gene provides partial protection against cytokine-induced cardiac dysfunction, iNOS-independent mechanisms, including contribution of NO from other NOS enzymes and the generation of superoxide, are also important contributors.
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PMID:The involvement of superoxide and iNOS-derived NO in cardiac dysfunction induced by pro-inflammatory cytokines. 1617 9

Kallistatin is a serine proteinase inhibitor that has been shown to reduce joint swelling and to inhibit inflammation in a rat model of arthritis. In this study, we investigated the effect and mechanisms of kallistatin on cardiac function after myocardial ischemia-reperfusion (I/R) injury. The human kallistatin gene in an adenoviral vector was delivered locally into rat heart 4 days before 30-min ischemia followed by 24-hr reperfusion. Kallistatin gene transfer significantly reduced myocardial infarct size and left ventricle end-diastolic pressure and improved cardiac contractility. Kallistatin significantly reduced I/R-induced cardiomyocyte apoptosis as identified by TUNEL and Hoechst staining, DNA laddering, cell viability, and caspase-3 activity in ischemic myocardium and in primary cultured cardiomyocytes. Kallistatin also reduced intramyocardial monocyte/macrophage and neutrophil accumulation in conjunction with decreased expression of monocyte chemoattractant protein-1, tumor necrosis factor-alpha, and intercellular adhesion molecule-1. Kallistatin delivery promoted cardiac endothelial nitric oxide synthase activation and increased nitric oxide (NO) formation, but inhibited NADH oxidase activity, p22phox expression, and superoxide production. Moreover, kallistatin reduced the phosphorylation of apoptosis signal-regulating kinase-1 and mitogen-activated protein kinases (MAPKs), but increased Akt and glycogen synthase kinase-3beta phosphorylation. The effects of kallistatin on cardiac function, oxidative stress, and these signal transduction events were all blocked by Nomega-nitro-L-argi-nine methyl ester. These results indicate a novel role of kallistatin in cardiac protection after I/R injury through increased NO formation and Akt-glycogen synthase kinase-3beta signaling and suppression of oxidative stress and MAPK activation.
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PMID:Novel role of kallistatin in protection against myocardial ischemia-reperfusion injury by preventing apoptosis and inflammation. 1708 Oct 80

We investigated the effect of tissue kallikrein infusion on cardiac protection at acute and sub-acute phases after myocardial infarction (MI). Immediately after MI, rats were infused with purified tissue kallikrein, with or without icatibant (a kinin B2 receptor antagonist). Intramyocardial injection of kallikrein reduced myocardial infarct size and inhibited cardiomyocyte apoptosis at 1 day after MI associated with increased nitric oxide levels, Akt and glycogen synthase kinase-3beta phosphorylation and decreased caspase-3 activation. Kallikrein infusion for 7 days improved cardiac function, normalized left ventricular wall thickness and decreased monocyte/macrophage infiltration in the infarct heart. Kallikrein treatment reduced NADH oxidase expression and activity, superoxide formation and malondialdehyde levels, and reduced MAPK and Ikappa-Balpha phosphorylation, NF-kappaB activation and MCP-1 and VCAM-1 expression. Kallikrein's effects were all blocked by icatibant. These results indicate that kallikrein through kinin B2 receptor activation prevents apoptosis, inflammation and ventricular remodeling by increased nitric oxide formation and suppression of oxidative stress-mediated signaling pathways.
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PMID:Tissue kallikrein infusion prevents cardiomyocyte apoptosis, inflammation and ventricular remodeling after myocardial infarction. 1719 72

Previous reports have described a tumor-associated NADH oxidase (tNOX) and its continuous activation in transformed culture cells. Certain anticancer drugs have been shown to inhibit preferentially both the tNOX activity and the growth of transformed culture cells and the cytotoxicity is associated with the induction of apoptosis. To investigate the biological function of tNOX protein, we have raised polyclonal antisera against bacterial expressed tNOX protein and the antisera are able to recognize protein bands in transformed cells but not the non-transformed cells tested. With tNOX antisera treatment, the survival in transformed cell lines is decreased but not the non-transformed cells. In addition, tNOX antisera-induced cytotoxicity is accompanied by the induction of apoptosis. However, slightly higher amount of PARP cleavage and activation of caspase-9 are observed in tNOX antisera treated HCT116 cells. Further experiments have demonstrated the activation of JNK and phosphorylation of p53 by treatment. In addition, tNOX antisera treatment leads to an impressive increase in reactive oxygen species in COS cells but not the control sera. Our data suggest that (a) tNOX antisera treatment may inhibit the growth of transformed cells by inducing apoptosis and (b) the apoptotic mechanism might be through modulating ROS production and JNK pathway.
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PMID:Effect of polyclonal antisera to recombinant tNOX protein on the growth of transformed cells. 1737 42

The exposure to non-thermal microwave electromagnetic fields generated by mobile phones affects the expression of many proteins. This effect on transcription and protein stability can be mediated by the MAPK (mitogen-activated protein kinase) cascades, which serve as central signalling pathways and govern essentially all stimulated cellular processes. Indeed, long-term exposure of cells to mobile phone irradiation results in the activation of p38 as well as the ERK (extracellular-signal-regulated kinase) MAPKs. In the present study, we have studied the immediate effect of irradiation on the MAPK cascades, and found that ERKs, but not stress-related MAPKs, are rapidly activated in response to various frequencies and intensities. Using signalling inhibitors, we delineated the mechanism that is involved in this activation. We found that the first step is mediated in the plasma membrane by NADH oxidase, which rapidly generates ROS (reactive oxygen species). These ROS then directly stimulate MMPs (matrix metalloproteinases) and allow them to cleave and release Hb-EGF [heparin-binding EGF (epidermal growth factor)]. This secreted factor activates the EGF receptor, which in turn further activates the ERK cascade. Thus this study demonstrates for the first time a detailed molecular mechanism by which electromagnetic irradiation from mobile phones induces the activation of the ERK cascade and thereby induces transcription and other cellular processes.
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PMID:Mechanism of short-term ERK activation by electromagnetic fields at mobile phone frequencies. 3306 40

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are closely linked to degenerative diseases such as Alzheimer's disease, Parkinson's, neuronal death including ischemic and hemorrhagic stroke, acute and chronic degenerative cardiac myocyte death, and cancer. As a byproduct of oxidative phosphorylation, a steady stream of reactive species emerge from our cellular energy plants, the mitochondria. ROS and RNS potentially cause damage to all cellular components. Structure alteration, biomolecule fragmentation, and oxidation of side chains are trade-offs of cellular energy production. ROS and RNS escape results in the activation of cytosolic stress pathways, DNA damage, and the upregulation of JNK, p38, and p53. Incomplete scavenging of ROS and RNS particularly affects the mitochondrial lipid cardiolipin (CL), triggers the release of mitochondrial cytochrome c, and activates the intrinsic death pathway. Due to the active redox environment and the excess of NADH and ATP at the inner mitochondrial membrane, a broad range of agents including electron acceptors, electron donors, and hydride acceptors can be used to influence the biochemical pathways. The key to therapeutic value is to enrich selective redox modulators at the target sites. Our approach is based on conjugating nitroxides to segments of natural products with relatively high affinity for mitochondrial membranes. For example, a modified gramicidin S segment was successfully used for this purpose and proven to be effective in preventing superoxide production in cells and CL oxidation in mitochondria and in protecting cells against a range of pro-apoptotic triggers such as actinomycin D, radiation, and staurosporine. More importantly, these mitochondria-targeted nitroxide/gramicidin conjugates were able to protect against apoptosis in vivo by preventing CL oxidation induced by intestinal hemorrhagic shock. Optimization of nitroxide carriers could lead to a new generation of effective antiapoptotic agents acting at an early mitochondrial stage. Alternative chemistry-based approaches to targeting mitochondria include the use of proteins and peptides, as well as the attachment of payloads to lipophilic cationic compounds, sulfonylureas, anthracyclines, and other agents with proven or hypothetical affinities for mitochondria. Manganese superoxide dismutase (MnSOD), SS tetrapeptides with 2',6'-dimethyltyrosine (Dmt) residues, rhodamine, triphenylphosphonium salts, nonopioid analgesics, adriamycin, and diverse electron-rich aromatics and stilbenes were used to influence mitochondrial biochemistry and the biology of aging. Some general structural principles for effective therapeutic agents are now emerging. Among these are the presence of basic or positively charged functional groups, hydrophobic substructures, and, most promising for future selective strategies, classes of compounds that are actively shuttled into mitochondria, bind to mitochondria-specific proteins, or show preferential affinity to mitochondria-specific lipids.
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PMID:Targeting mitochondria. 1819 22

The cell adhesion receptor, syndecan-4, regulates cellular interactions with both the extracellular matrix and soluble ligands. Accumulating evidence also suggests that cell adhesion is involved in generating reactive oxygen species (ROS). Here, we investigated the role of syndecan-4 in regulating growth factor-induced ROS generation. Rat embryo fibroblasts (REFs) overexpressing syndecan-4 exhibited increased ROS levels compared to control cells. Expression of the non-phagocytic NADH oxidase component Nox1 was increased in syndecan-4-overexpressing REFs and syndecan-4-mediated ROS generation was diminished when levels of Nox1 were knocked-down with small inhibitory RNAs. In addition, syndecan-4 enhanced platelet-derived growth factor (PDGF)-induced MAP kinase activity in parallel with ROS generation. Collectively, these data suggest that syndecan-4 regulates PDGF-induced MAP kinase activation by altering ROS generation.
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PMID:Syndecan-4 regulates platelet-derived growth factor-mediated MAP kinase activation by altering intracellular reactive oxygen species. 1861 65


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