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)

Doxorubicin (DOX) is widely used to treat patients suffering from cancer, but the usage for patients is limited because of the dose-dependent cardiotoxicity. We hypothesized that DOX induces apoptosis through caspase activation in cardiomyocytes, and we examined this hypothesis using both rat primary cultured cardiomyocytes and rat hearts from an animal model. Cardiomyocytes were treated with DOX for 24 h. The activity of caspase-3 was significantly increased by DOX treatment. In rats with DOX injected intravenously once a week for 5 weeks, left ventricular fractional shortening evaluated by echocardiography was significantly decreased at age 14 weeks, 2 weeks after the end of DOX-administration. At 16 weeks of age, endothelin-1 mRNA and atrial natriuretic peptide mRNA were also significantly increased, likewise, and TUNEL positive cells were significantly increased in the ventricles of DOX-treated rats. The activity of caspase-3 in the ventricles was also significantly increased compared to that of untreated rats at 16 weeks. However, the activity of caspase-8 and the expression level of Fas-ligand mRNA were comparable with those of the untreated rats. In conclusion, DOX induces apoptosis through the activation of caspase-3, suggesting that apoptosis has an important role in the progression of cardiomyopathy due to DOX.
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PMID:Doxorubicin induces apoptosis by activation of caspase-3 in cultured cardiomyocytes in vitro and rat cardiac ventricles in vivo. 1676 56

The polyphenol epigallocatechin-3-gallate (EGCG), the principal mediator of the green tea, has been known to possess antitumor effect. The endothelin A receptor (ET(A)R)/endothelin-1 (ET-1) axis is overexpressed in ovarian carcinoma representing a novel therapeutic target. In this study, we examined the green tea and EGCG effects on two ovarian carcinoma cell lines, HEY and OVCA 433. EGCG inhibited ovarian cancer cell growth and induced apoptosis that was associated with a decrease in Bcl-X(L) expression and activation of caspase-3. Treatment with green tea or EGCG inhibited ET(A)R and ET-1 expression and reduced the basal and ET-1-induced cell proliferation and invasion. The EGCG-induced inhibitory effects were associated with a decrease of ET(A)R-dependent activation of the p42/p44 and p38 mitogen-activated protein kinases and phosphatidylinositol 3-kinase pathway. Remarkably, EGCG treatment resulted in a lowering of basal and ET-1-induced angiogenesis and invasiveness mediators, such as vascular endothelial growth factor and tumor proteinase activation. Finally, in HEY ovarian carcinoma xenografts, tumor growth was significantly inhibited by oral administration of green tea. This effect was associated with a reduction in ET-1, ET(A)R, and vascular endothelial growth factor expression, microvessel density, and proliferation index. These results provide a novel insight into the mechanism by which EGCG, affecting multiple ET(A)R-dependent pathways, may inhibit ovarian carcinoma growth, suggesting that EGCG may be useful in preventing and treating ovarian carcinoma in which ET(A)R activation by ET-1 plays a critical role in tumor growth and progression.
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PMID:Green tea polyphenol epigallocatechin-3-gallate inhibits the endothelin axis and downstream signaling pathways in ovarian carcinoma. 1681 7

Soft tissue trauma and hemorrhage (T-H) diminishes various aspects of liver function, while it increases hepatic nitrate/nitrite, inducible nitric oxide synthase (iNOS), and endothelin-1 levels. Treatment with androstenediol (AED) inhibits the T-H-induced alterations of the above parameters. We sought to identify the molecular events underlying the beneficial effect of AED. Exposure of rats to T-H significantly increased the caspase-3 activity and protein, whereas treatment with AED significantly limited these increases. AED treatment also suppressed the T-H-induced increase in iNOS by effectively altering the levels of key transcription factors involved in the regulation of iNOS expression. Immunoprecipitation and immunoblotting analyses indicate that T-H increased apoptosome formation, and AED treatment significantly decreased it. Modulating the iNOS protein by transfecting cells with iNOS gene or small interfering RNA further confirmed the correlation between iNOS and caspase-3. Our data indicate that AED limits caspase-3 expression by suppressing the expression of transcription factors involved in the production of iNOS, resulting in decreased apoptosome. AED can potentially be a useful adjuvant for limiting liver apoptosis following T-H shock.
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PMID:Androstenediol inhibits the trauma-hemorrhage-induced increase in caspase-3 by downregulating the inducible nitric oxide synthase pathway. 1711 May 8

Oxidative stress has been implicated in cell death in range of disease states including ischemia/reperfusion injury of the heart and heart failure. Here we have investigated the mechanisms of cell death following chronic exposure of cardiac myocytes to oxidative stress initiated by hydrogen peroxide. This exposure induced a delayed form of cell death with ultrastructural changes typical of necrosis, and that was accompanied by the release of lactate dehydrogenase and increased lipid peroxidation. However, this delayed death was not accompanied by the loss of mitochondrial membrane potential or caspase-3 activation. Furthermore, we could demonstrate that this delayed necrosis was at least partially prevented by pre-treatment with the hypertrophic stimuli endothelin-1 or leukemic inhibitory factor. Our results suggest that this delayed form necrosis may also comprise an ordered series of events involving pathways amenable to therapeutic modulation.
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PMID:Necrotic death without mitochondrial dysfunction-delayed death of cardiac myocytes following oxidative stress. 1720 43

Previously, we reported that transgenic mice overexpressing endothelin-1 in astrocytes showed more severe neurological deficits and increased infarct after transient focal ischemia. In those studies, we also observed increased level of aldose reductase (AR), the first and rate-limiting enzyme of the polyol pathway, which has been implicated in osmotic and oxidative stress. To further understand the involvement of the polyol pathway, the mice with deletion of enzymes in the polyol pathway, AR, and sorbitol dehydrogenase (SD), which is the second enzyme in this pathway, were challenged with similar cerebral ischemic injury. Deletion of AR-protected animals from severe neurological deficits and large infarct, whereas similar protection was not observed in mice with SD deficiency. Most interestingly, AR(-/-) brains showed lowered expression of transferrin and transferrin receptor with less iron deposition and nitrotyrosine accumulation. The protection against oxidative stress in AR(-/-) brain was also associated with less poly(adenosine diphosphate-ribose) polymerase (PARP) and caspase-3 activation. Pharmacological inhibition of AR by Fidarestat also protected animals against cerebral ischemic injury. These findings are the first to show that AR contributes to iron- and transferrin-related oxidative stress associated with cerebral ischemic injury, suggesting that inhibition of AR but not SD may have therapeutic potential against cerebral ischemic injury.
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PMID:Deletion of aldose reductase leads to protection against cerebral ischemic injury. 1729 45

Many space missions have shown that prolonged space flights may increase the risk of cardiovascular problems. Using a three-dimensional clinostat, we investigated human endothelial EA.hy926 cells up to 10 days under conditions of simulated microgravity (microg) to distinguish transient from long-term effects of microg and 1g. Maximum expression of all selected genes occurred after 10 min of clinorotation. Gene expression (osteopontin, Fas, TGF-beta(1)) declined to slightly upregulated levels or rose again (caspase-3) after the fourth day of clinorotation. Caspase-3, Bax, and Bcl-2 protein content was enhanced for 10 days of microgravity. In addition, long-term accumulation of collagen type I and III and alterations of the cytoskeletal alpha- and beta-tubulins and F-actin were detectable. A significantly reduced release of soluble factors in simulated microgravity was measured for brain-derived neurotrophic factor, tissue factor, vascular endothelial growth factor (VEGF), and interestingly for endothelin-1, which is important in keeping cardiovascular balances. The gene expression of endothelin-1 was suppressed under microg conditions at days 7 and 10. Alterations of the vascular endothelium together with a decreased release of endothelin-1 may entail post-flight health hazards for astronauts.
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PMID:Modeled gravitational unloading induced downregulation of endothelin-1 in human endothelial cells. 1734 Jun 22

We hypothesized that progressive decline in myocardial performance would correlate with upregulation of markers for apoptotic mechanisms following increased duration of polymicrobial sepsis in the rat. Male Sprague-Dawley rats (350-400 g) were randomized into sham, 1-, 3- and 7-day sepsis groups. Each septic rat received 200 mg/kg cecal inoculum intraperitoneally (i.p). The post-mortem analysis showed a severely inflamed peritoneum with the presence of pus in all septic animals that was directly proportional to the duration of sepsis. We observed 10, 33 and 42% mortality in the 1-, 3- and 7-day sepsis groups, respectively. Septic animals at 3 and 7 days exhibited an increased wet lung/total body weight and heart weight/total body weight. A significant increase in total cardiac troponin I (cTnI) and C Reactive Protein (CRP) and endothelin-1 (ET-1) was also observed with an increased duration of sepsis. Myocardial ET-1 concentration in the 7-day post-sepsis group was significantly elevated compared to the sham and 1-day post-sepsis groups. Sepsis also produced a significant decrease in the mean arterial pressure in the 7-day post-sepsis group and tachycardia in the 1-, 3-, and 7-day post-sepsis groups compared to the sham group. A significant prolongation of the left ventricular isovolumic relaxation rate constant, tau, and left ventricular end-diastolic pressure in the 1-, 3- and 7-day post-sepsis groups compared to the sham group was observed. In addition, a significant decrease in the rates of left ventricular relaxation (-dP/dt) and contraction (+dP/dt) in the 3- and 7-day post-sepsis groups compared to the sham and 1-day post-sepsis group was observed. Sepsis produced a significant upregulation in the expression of myocardial TRADD, cytosolic active caspase-3, the Bax/Bcl(2) ratio, and the mitochondrial release of cytochrome C in the 3- and 7-day post-sepsis groups. We observed a progressive increase in the number of TUNEL positive nuclei, cytosolic caspase-3 activation and co-localization of PARP in the nuclei at 1, 3 and 7 days post-sepsis. These data suggest that the progression of sepsis from 1 day to 3-7 days produce distinct cardiodynamic characteristics with a more profound effect during later stages. The sepsis-induced decline in myocardial performance correlates with the induction of myocardial apoptosis.
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PMID:Distinct cardiodynamic and molecular characteristics during early and late stages of sepsis-induced myocardial dysfunction. 1761 71

EPO (erythropoietin) has recently been shown to have protective actions upon the myocardium; however, the direct effects of EPO upon cardiac contractile and secretory functions are unknown and the signalling mechanisms are not well defined. In the present study, we provide the first evidence of direct cardiac contractile actions of EPO. In isolated perfused Sprague-Dawley rat hearts, a 30 min infusion of EPO significantly increased contractility in a dose-dependent fashion (maximal change 18+/-2% with 1 unit/ml EPO; P<0.005 compared with vehicle). Perfusate ET-1 (endothelin-1) increased transiently during EPO infusion, and the ET(A/)ET(B) antagonist bosentan abolished the inotropic response to EPO. BNP (B-type natriuretic peptide) secretion (28+/-8%; P<0.05) and nuclear transcription factor GATA-4 DNA-binding activity (51%; P<0.05) were both significantly increased by EPO and blocked by bosentan. In a model of global ischaemic injury, delivery of 1 unit/ml EPO during reperfusion significantly attenuated creatine kinase release (28+/-12%; P<0.05) and significantly improved contractile recovery (P<0.001), independent of ET(A) blockade. Apoptotic indices [assessed by TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling)/cleaved caspase-3-positive cells] were significantly decreased (P<0.01) by 1 unit/ml EPO during reperfusion alone, coincident with significantly increased phosphorylation of myocardial JAK2 (Janus kinase 2) and STAT3 (signal transducer and activator of transcription 3). Thus EPO directly enhances cardiac contractility and BNP secretion and alleviates ischemia/reperfusion injury via ET-1-dependent and -independent mechanisms respectively.
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PMID:Direct cardiac actions of erythropoietin (EPO): effects on cardiac contractility, BNP secretion and ischaemia/reperfusion injury. 1791 23

Fibroblast growth factors interact with appropriate endothelial cell (EC) surface receptors and initiate intracellular signal cascades, which participate in modulating blood vessel growth. EC, upon exposure to basic fibroblast growth factors (bFGFs) undergo profound functional alterations, which depend on their actual sensitivity and involve gene expression and de novo protein synthesis. We investigated the effects of bFGF on signaling pathways of EA.hy926 cells in different environments. EC were cultured under normal gravity (1 g) and simulated microgravity (micro g) using a three-dimensional (3D) clinostat. Microgravity induced early and late apoptosis, extracellular matrix proteins, endothelin-1 (ET-1) and TGF-beta(1) expression. Microgravity reduced eNOS mRNA within 24 h. Moreover, a six- to eightfold higher amount of IL-6 and IL-8 was secreted within 24 h micro g. In addition, microgravity induced a duplication of NF-kappaB p50, while p65 was quadrupled. At 1 g, bFGF application (4 h) reduced ET-1, TGF-beta(1) and eNOS gene expression. After 24 h, bFGF enhanced fibronectin, VEGF, Flk-1, Flt-1, the release of IL-6, IL-8, and TGF-beta(1). Furthermore, bFGF promoted apoptosis, reduced NFkB p50, but enhanced NFkB p65. After 4 h micro g, bFGF decreased TGF-beta(1), eNOS, and ET-1 gene expression. After 24 h micro g, bFGF elevated fibronectin, Flk-1 and Flt-1 protein, and reduced IL-6 and IL-8 compared with vehicle treated micro g cultures. In micro g, bFGF enhanced NF-KappaB p50 by 50%, Bax by 25% and attenuated p65, activation of caspase-3 and annexin V-positive cells. bFGF differently changes intracellular signals in ECs depending whether it is applied under microgravity or normal gravity conditions. In microgravity, bFGF contributes to protect the EC from apoptosis.
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PMID:Effects of basic fibroblast growth factor on endothelial cells under conditions of simulated microgravity. 1825 36

The mechanisms linking diabetes to plaque rupture and thrombotic occlusion remain largely speculative, yet matrix metalloproteinases (MMP) and endothelial apoptosis may represent central elements. Binding of oxidized low-density lipoprotein (oxLDL) to endothelial lectin-like oxidized LDL receptor-1 (LOX-1) induces oxidative stress, MMP expression and apoptosis. In the present study, we examined the effect of gliclazide, a second generation sulfonylurea with antioxidant properties, on LOX-1 expression and LOX-1-mediated MMP-9 expression and apoptosis in oxLDL-treated human aortic endothelial cells (HAECs). Incubation of HAECs with oxLDL increased LOX-1 expression and enhanced MMP-9 production by these cells. Treatment with an anti-LOX-1 antibody or with antioxidants, including gliclazide, inhibited these effects. Induction of LOX-1 and LOX-1-mediated MMP-9 production involved endothelin-1 production and nuclear factor-kappaB activation. These biological parameters were inhibited by gliclazide and anti-LOX-1 antibody treatment. In HAECs, oxLDL induced apoptosis, an effect associated with reduced protein kinase B (PKB) activity. Anti-LOX-1 antibody, antioxidants including gliclazide, as well as caspase inhibitors prevented oxLDL-induced apoptosis. The anti-apoptotic effect of gliclazide was associated with an increase in PKB activity and a decrease in caspase-3 and -9 activities. These results demonstrate that gliclazide inhibits endothelial LOX-1 expression and prevents LOX-1-mediated proatherogenic effects associated with endothelial dysfunction and plaque rupture.
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PMID:The oral anti-diabetic agent, gliclazide, inhibits oxidized LDL-mediated LOX-1 expression, metalloproteinase-9 secretion and apoptosis in human aortic endothelial cells. 1880 83


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