Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1 Endothelin-1 (ET-1), an endothelium-derived vasoactive peptide, participates in the regulation of endothelial function through mechanisms that are not fully elucidated. This study examined the impact of ET-1 on oxidative stress, apoptosis and cell proliferation in human umbilical vein endothelial cells (HUVEC). HUVECs were challenged for 24 h with ET-1 (10 pM-10 nM) in the absence or presence of the ET(B) receptor antagonist BQ788 (1 microM) or the NADPH oxidase inhibitor apocynin (1 microM). Reactive oxygen species (ROS) were detected using chloromethyl-2',7'-dichlorodihydrofluorescein diacetate. Apoptosis was evaluated with 4',6'-diamidino-2'-phenylindoladihydrochloride staining and by the caspase-3 assay. Cell proliferation was measured by a colorimetric assay. Expression of NADPH oxidase, Akt, pAkt, Bcl-2, Bax, IkappaB, caveolin-1 and eNOS was evaluated by Western blot analysis. 2 ET-1 significantly enhanced ROS generation and cell proliferation following 24-h incubation, both of which were prevented by BQ788 or apocynin, consistent with the ability of ET-1 to directly upregulate NADPH oxidase. ET-1 itself did not affect apoptosis but attenuated homocysteine-induced apoptosis through an ET(B) receptor-mediated mechanism. Western blot analysis indicated that ET-1 alleviated homocysteine (Hcy)-induced apoptosis, likely acting by antagonizing the Hcy-induced decreases in Akt, pAkt, pAkt-to-Akt, Bcl-2-to-Bax ratios and increases in Bax and caveolin-1 expression. Furthermore, ET-1 downregulated expression of caveolin-1 and eNOS, which was attenuated by BQ788 or apocynin. 3 In summary, our results suggest that ET-1 affects oxidative stress, proliferation and apoptosis possibly through ET(B), NADPH oxidase, Akt, Bax and caveolin-1-mediated mechanisms.
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PMID:Endothelin-1 enhances oxidative stress, cell proliferation and reduces apoptosis in human umbilical vein endothelial cells: role of ETB receptor, NADPH oxidase and caveolin-1. 1576

In the present study, we examined the molecular mechanism by which homocysteine causes neuronal cell apoptosis. We further investigated the mechanisms of melatonin's ability to reduce homocysteine-induced apoptosis. Consistent with its antioxidant properties, melatonin reduced homocysteine-induced lipid peroxidation and stimulated glutathione peroxidase enzyme activity in hippocampus of rats with hyperhomocysteinemia. Furthermore, melatonin treatment diminished cytochrome c release from mitochondria and reduced caspase 3 and caspase 9 activation induced by hyperhomocysteinemia. Chronic hyperhomocysteinemia also led to poly(ADP-ribose) polymerase cleavage and subsequently DNA fragmentation. Treatment with melatonin markedly inhibited poly(ADP-ribose) polymerase cleavage and reduced DNA damage. Hyperhomocysteinemia caused an elevation of pro-apoptotic Bax levels while reducing anti-apoptotic protein, Bcl-2, levels. Daily administration of melatonin up-regulated Bcl-2 and down-regulated Bax levels. We propose that, in addition to its antioxidant properties, melatonin has the ability to protect neuronal cells against apoptosis mediated homocysteine neurotoxicity by modulating apoptosis-regulatory proteins in the hippocampus of rats.
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PMID:Melatonin inhibits neural apoptosis induced by homocysteine in hippocampus of rats via inhibition of cytochrome c translocation and caspase-3 activation and by regulating pro- and anti-apoptotic protein levels. 1621 88

Previous studies from our laboratory have shown that ethanol consumption results in an increase in hepatocellular S-adenosylhomocysteine levels. Because S-adenosylhomocysteine is a potent inhibitor of methylation reactions, we propose that increased intracellular S-adenosylhomocysteine levels could be a major contributor to ethanol-induced pathologies. To test this hypothesis, hepatocytes isolated from rat livers were grown on collagen-coated plates in Williams' medium E containing 5% FCS and exposed to varying concentrations of adenosine in order to increase intracellular S-adenosylhomocysteine levels. We observed increases in caspase-3 activity following exposure to adenosine. This increase in caspase activity correlated with increases in intracellular S-adenosylhomocysteine levels and DNA hypoploidy. The adenosine-induced changes could be significantly attenuated by betaine administration. The mechanism of betaine action appeared to be via the methylation reaction catalyzed by betaine-homocysteine-methyltransferase. To conclude, our results indicate that the elevation of S-adenosylhomocysteine levels in the liver by ethanol is a major factor in altering methylation reactions and in increasing apoptosis in the liver. We conclude that ethanol-induced alteration in methionine metabolic pathways may play a crucial role in the pathologies associated with alcoholic liver injury and that betaine administration may have beneficial therapeutic effects.
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PMID:Role of elevated S-adenosylhomocysteine in rat hepatocyte apoptosis: protection by betaine. 1625 11

An elevated level of homocysteine (Hcy) limits the growth and induces apoptosis. However, the mechanism of Hcy-induced programmed cell death in endothelial cells is largely unknown. We hypothesize that Hcy induces intracellular reactive oxygen species (ROS) production that leads to the loss of transmembrane mitochondrial potential (Deltapsi(m)) accompanied by the release of cytochrome-c from mitochondria. Cytochrome-c release contributes to caspase activation, such as caspase-9, caspase-6, and caspase-3, which results in the degradation of numerous nuclear proteins including poly (ADP-ribose) polymerase (PARP), which subsequently leads to the internucleosomal cleavage of DNA, resulting cell death. In this study, rat heart microvascular endothelial cells (MVEC) were treated with different doses of Hcy at different time intervals. Apoptosis was measured by DNA laddering and transferase-mediated dUTP nick-end labeling (TUNEL) assay. ROS production and MP were determined using fluorescent probes (2,7-dichlorofluorescein (DCFH-DA) and 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethyl-benzamidazolocarbocyanin iodide (JC-1), respectively, by confocal microscopy. Differential gene expression for apoptosis was analyzed by cDNA array. The results showed that Hcy-mediated ROS production preceded the loss of MP, the release of cytochrome-c, and the activation of caspase-9 and -3. Moreover the Hcy treatment resulted in a decrease in Bcl(2)/Bax ratio, evaluated by mRNA levels. Caspase-9 and -3 were activated, causing cleavage of PARP, a hallmark of apoptosis and internucleosomal DNA fragmentation. The cytotoxic effect of Hcy was blocked by using small interfering RNA (siRNA)-mediated suppression of caspase-9 in MVEC. Suppressing the activation of caspase-9 inhibited the activation of caspase -3 and enhanced the cell viability and MP. Our data suggested that Hcy-mediated ROS production promotes endothelial cell death in part by disturbing MP, which results in subsequent release of cytochrome-c and activation of caspase-9 and 3, leading to cell death.
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PMID:Mitochondrial mechanism of microvascular endothelial cells apoptosis in hyperhomocysteinemia. 1651 65

This study determined whether exercise training prevents pathological hypertrophy in the left ventricle by modulation of myocardial and apoptosis-associated genes. We used spontaneously hypertensive rats (n=15, non-exercise SHR), exercise-trained SHR (n=15, treadmill exercise for 12 weeks), and sedentary Wistar-Kyoto (WKY) rats (n=15). Exercise-trained SHR expressed adaptive changes such as reduced body weight, heart rate, blood pressures, left ventricle wall thickness, lipid profiles, and homocysteine level. The mRNA expression of angiotensin converting enzyme, endothelin-1, and brain natriuretic peptides in the heart was lower in the exercise-trained SHR and in the WKY than in the non-exercise SHR, whereas mRNA expression of caveolin-3 and eNOS in the heart was higher. Bcl-2 protein was higher in the exercise-trained SHR than in the WKY and the non-exercise SHR. In contrast, Bax protein levels were lower in the exercise-trained SHR and in the WKY than in the non-exercise SHR. Furthermore, the levels of the active forms of caspase-3 (20 kDa) were lower in the exercise-trained SHR and in the WKY than in the non-exercise SHR. These findings suggest that exercise training prevents pathological hypertrophy in the left ventricle by modulation of myocardial genes and that it interferes with a signal transduction pathway of apoptosis secondary to the pathological cardiac hypertrophy.
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PMID:Effects of exercise training on pathological cardiac hypertrophy related gene expression and apoptosis. 1658 33

Hyperhomocysteinemia is an independent risk factor for the development of atherosclerosis. However the underlying mechanisms responsible for endothelial cell injury with increased plasma concentration of homocysteine or homocysteine derivatives remains still incompletely elucidated. In this study, we investigated the ability of homocysteine (Hcy) and homocysteine thiolactone (HcyT) to induce cell death and IL-8 secretion in primary human umbilical vein endothelial cells (HUVEC). Hcy and HcyT were both cytotoxic and capable of promoting cell death, as measured by caspase-3 activation and DNA fragmentation. ELISA assays clearly demonstrated that Hcy and HcyT strongly activated IL-8 release. Furthermore, our results showed that HcyT was much more efficient than Hcy in activating caspase-3 or in inducing IL-8 secretion. The use of antioxidants such as vitamin C and vitamin E strongly but not completely reduced programmed cell death and chemokine release suggesting that other pathways different than reactive oxygen species are also involved. This study suggests that Homocysteine derivatives like HcyT might possess stronger cytotoxicity and pro-inflammatory properties and that Hcy derivatives levels should therefore be more taken into account during diagnostics.
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PMID:Comparative study on in vitro effects of homocysteine thiolactone and homocysteine on HUVEC cells: evidence for a stronger proapoptotic and proinflammative homocysteine thiolactone. 1671 83

The effects of exogenous glycine on homocysteine (HoCys)-induced reductions in chick (Gallus gallus) embryo viability, HoCys-induced increases in brain and hepatic membrane lipid peroxidation, HoCys-induced apoptosis (caspase-3 activities) in brain and hepatic tissues, and HoCys-induced reductions in brain and hepatic S-adenosylemethionine (SAM)/S-adenosylhomocysteine (SAH) levels were studied. Exogenous HoCys caused reductions in percent living embryos and reductions in embryo masses. Exogenous glycine attenuated these HoCys-induced reductions in embryo viability. Brain and liver tissues of HoCys-treated embryos exhibited increased caspase-3 activities, increased lipid hydroperoxide (LPO) levels, and reduced levels of long-chain polyunsaturated membrane fatty acids. While exogenous glycine attenuated HoCys-induced changes in brain caspase-3 activities, brain LPO levels, and brain membrane PUFA levels, exogenous glycine was less effective in attenuating HoCys-induced changes in hepatic caspase-3 activities and hepatic membrane PUFA levels. HoCys-induced reductions in SAM/SAH ratios were observed in brains and livers. Exogenous glycine attenuated HoCys-induced reductions in brain SAM/SAH. However, glycine was unable to attenuate HoCys-induced reductions in hepatic SAM/SAH levels.
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PMID:Exogenous glycine partially attenuates homocysteine-induced apoptosis and membrane peroxidation in chick embryos. 1680 69

Homocysteine (Hcy) appears to exert different effects on immune functions possibly contributing to age-related pathological states, including vascular diseases, immune dysfunction, and Alzheimer's disease. However, molecular mechanisms underlying Hcy toxicity need to be better characterized. Since T cells are a suitable model to address the possible role of replicative senescence during the in vivo aging, we investigated the effects of high Hcy concentrations on mitogen-activated lymphocytes, with regard to evaluation of DNA damage and cell cycle alterations. Cultured human peripheral blood lymphocytes were stimulated with mitogenic concanavalin A (5 microg/ml) for 48 h in the presence or absence of Hcy (1 mM). Both flow cytometric analysis and caspase-3 activity assay showed an increased rate of apoptosis in Hcy-treated lymphocyte cultures compared to controls. Further, Hcy exposure caused DNA fragmentation as evaluated by single cell gel electrophoresis showing the occurrence of comets. Cytokinesis-block micronucleus assay, performed after addition of cytochalasin B (5 microg/ml) and incubation up to 72 h, revealed a significantly higher frequency of micronucleated/binucleated cells in Hcy-treated cultures compared to controls (P < 0.001). Hcy also reduced cyclin B expression in comparison to control cultures, while cyclin D levels were not significantly affected. Cell cycle alterations, such as the inability of cells to enter into mitosis, could be related with DNA damage. These findings provided a link between perturbation of lymphocyte proliferation homeostasis and commitment towards apoptosis. Our results suggest the involvement of Hcy in the altered immune function associated with age and disease pathology.
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PMID:Homocysteine induces DNA damage and alterations in proliferative capacity of T-lymphocytes: a model for immunosenescence? 1696 6

Elevated plasma homocysteine levels are associated with the risk of atherosclerosis and arterial and venous thrombosis. We have previously demonstrated that rabbits rendered hyperhomocysteinemic by parenteral administration of homocysteine develop a dysfibrinogenemia that is associated with the formation of fibrin clots that are abnormally resistant to fibrinolysis. We suggested that this acquired dysfibrinogenemia contributes to the thrombotic tendency in hyperhomocysteinemia. However, it was possible that the homocysteine-associated dysfibrinogenemia was an artifact of the parenteral administration model. Therefore, the goals of the current study were to develop a diet-induced model of homocysteinemia in rabbits and determine whether a dysfibrinogenemia and evidence of oxidative stress develop in this model as they do when homocysteine is injected. We found that rabbits fed a diet severely deficient in folate and mildly deficient in choline develop mild hyperhomocysteinemia: 14.8+/-4.0 microM in deficient rabbits compared to 9.0+/-1.7 microM in controls. The deficient rabbits also develop evidence of oxidant stress: increased lipid peroxidation in liver, impaired mitochondrial enzyme activities in liver and elevated caspase-3 levels in plasma. Most importantly, the deficient rabbits also develop a dysfibrinogenemia characterized by increased resistance to fibrinolysis. We believe that this dietary model of homocysteinemia is clinically relevant and reproduces many features associated with hyperhomocysteinemia in previous work using in vitro and in vivo models. Our findings suggest that an acquired dysfibrinogenemia could play a role in the increased risk of atherothrombotic disease in mildly hyperhomocysteinemic human subjects.
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PMID:Pro-thrombotic and pro-oxidant effects of diet-induced hyperhomocysteinemia. 1697 25

Hyperhomocysteinemia is prevalent among patients with chronic kidney disease (CKD) and has been linked to progressive kidney and vascular diseases. Increased glomerular mesangial cell (MC) turnover, including proliferation and apoptosis, is a hallmark of CKD. Activation of p38-mitogen-activated protein kinase (p38-MAPK) has been linked to apoptosis in many cell lines. Accordingly, we studied the effect of homocysteine (Hcy) on MC p38-MAPK signalling and apoptosis. Hcy (50 microM/24 h) increased MC apoptosis as determined by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) nick end labelling (TUNEL) and single-stranded DNA (ssDNA) analysis. In addition to increases in pro-caspase-3 protein and caspase-3 activity, cells exposed to Hcy manifested enhanced reactive oxygen species content. Hcy increased p38-MAPK activity (fivefold), with maximal effect at 50 microM and 20 min; p38-MAPK activation was attenuated by N-acetylcysteine (Nac) and catalase (Cat), further indicating that the effect was via oxidative stress. Confocal microscopy revealed activation and nuclear translocation of p38-MAPK that was attenuated by Cat. In addition, Hcy-induced apoptosis as determined by TUNEL and ssDNA assay was abrogated by Nac, Cat, and SB203580 (p38-MAPK inhibitor). We conclude that in MC, Hcy (i) activates p38-MAPK and increases p38MAPK nuclear translocation via an oxidative stress dependent mechanism and (ii) induces DNA damage and apoptosis that is dependent on oxidative stress and p38-MAPK activation.
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PMID:Homocysteine induces mesangial cell apoptosis via activation of p38-mitogen-activated protein kinase. 1714 72


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