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)

It has been reported that apoptosis is a significant contributor to myocardial cell death as a result of reperfusion injury. However, whether the extent of cardiomyocyte apoptosis following ischemia and reperfusion varies in different pathophysiological backgrounds is still uncertain. In this study, we examined whether hypercholesterolemia increases the extent of myocardial reperfusion injury by aggravating cardiomyocyte apoptosis and the effects of hypercholesterolemia on the expression of Bcl-2 and Bax proteins and the activation of caspase-3. Twenty-eight male New Zealand white rabbits were fed standard chow (control, n = 14) or chow supplemented with 10% cholesterol (hypercholesterolemic, n = 14) for 8 wk. Anesthetized rabbits were then subjected to 30 min of left circumflex artery occlusion followed by 4 h of reperfusion. Apoptosis was identified as "DNA ladders" by gel electrophoresis and confirmed histologically using the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay. The infarct size (% of risk region) was significantly greater in hypercholesterolemic rabbits than in controls (39 +/- 6 vs. 23 +/- 2%, P = 0.02). Very few TUNEL-positive cardiomyocytes could be identified in the nonischemic regions in both groups, consistent with an absence of DNA laddering. In contrast, TUNEL-positive cardiomyocytes were significantly displayed in the ischemic, nonnecrotic myocardium, and DNA ladder occurred in all animals. The percentage of TUNEL-positive cardiomyocytes in the ischemic nonnecrotic myocardium was significantly higher in hypercholesterolemic rabbits compared with controls (40 +/- 5 vs. 17 +/- 11%, P < 0.001). Western blot analysis showed that, in the nonischemic myocardium, hypercholesterolemic rabbits exhibited an approximately 50% increase in the expression of Bcl-2 (P < 0.05), but not Bax, than control rabbits. However, compared with controls, hypercholesterolemic rabbits exhibited a more pronounced decrease in the expression of Bcl-2 (42 +/- 4 vs. 26 +/- 2%, P < 0.01) and a similar extent of increase in the expression of Bax in the ischemic myocardium. Furthermore, hypercholesterolemic rabbits were associated with a markedly increased activation of caspase-3 within the ischemic myocardium compared to control rabbits. This study demonstrates that although hypercholesterolemia is associated with an increased myocardial Bcl-2/Bax ratio at baseline, it still significantly exacerbates cardiac reperfusion injury, not only by increasing the infarct size but also by increasing the extent of cardiomyocyte apoptosis.
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PMID:Increased cardiomyocyte apoptosis following ischemia and reperfusion in diet-induced hypercholesterolemia: relation to Bcl-2 and Bax proteins and caspase-3 activity. 1203 Mar 19

The risk of atherosclerosis is intimately related to the heterogeneity of low-density lipoprotein (LDL) particles. The potential relationship between oxidative modification of distinct LDL subspecies and induction of apoptosis in arterial wall cells is indeterminate. The capacity of light LDL3 versus dense LDL5 to induce cytotoxicity in endothelial cells as a function of the degree of copper-mediated oxidation was compared. Mildly oxidized LDL3 (oxLDL3) exerted potent cytotoxicity, which was intimately related to both the degree of oxidation and the oxLDL3 concentration based on either cholesterol content or particle number. In contrast, dense LDL5 particles exerted a minor effect on cell viability. Cells incubated with oxLDL3 exhibited apoptotic features, with cytoplasmic condensation, cell or nuclear fragmentation, and accumulation of DNA fragments. OxLDL3-induced apoptosis involved cytoplasmic release of cytochrome c, with a concomitant increase in caspase-3-like protease activity. OxLDL3 particles were uniquely distinct from oxLDL5 particles in their elevated content of lipid hydroperoxides. Hydroperoxide removal by NaBH4 markedly reduced oxLDL3-induced cytotoxicity, leading to an increase in cell viability. Lipid hydroperoxide content of oxidatively modified LDL subclasses is therefore a major determinant of the induction of apoptosis in endothelial cells. These data are highly relevant to atherogenic hypercholesterolemia, in which the LDL phenotype is dominated by elevated concentrations of light LDL3.
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PMID:Mildly oxidized LDL particle subspecies are distinct in their capacity to induce apoptosis in endothelial cells: role of lipid hydroperoxides. 1247 9

1. Hypercholesterolaemia has been shown to be associated with greater myocardial ischaemia-reperfusion injury, in which apoptosis and inflammation-mediated necrosis both play a key role. 2. Caspase-1 is involved in the activation of both apoptosis and inflammation, through the intermediate of interleukin-1beta (IL-1beta). We herein examined whether pharmacological inhibition of the caspase-1 cascade, using Ac-Tyr-Val-Ala-Asp-CH(2)Cl (Ac-YVAD.cmk), after myocardial ischaemia have greater protective effects on myocardial ischaemia-reperfusion injury in diet-induced hypercholesterolaemic rabbits. 3. Male rabbits fed with standard chow or chow supplemented with 0.5% cholesterol and 10% coconut oil for 8 weeks were subjected to 30 min of left circumflex artery occlusion followed by 4 h of reperfusion. An intravenous bolus of Ac-YVAD.cmk (1.6 mg kg(-1)) or vehicle was given 20 min after coronary occlusion. 4. Postischaemic administration of Ac-YVAD.cmk markedly decreased infarct size from 26+/-3% to 12+/-2% in normally fed rabbits (P=0.005) and from 41+/-6% to 14+/-2% in cholesterol-fed rabbits (P<0.001). 5. In the ischaemic non-necrotic area, treatment with Ac-YVAD.cmk markedly reduced the percentage of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling (TUNEL)-positive cardiomyocytes from 15.5+/-0.8% to 2.2+/-0.1% in normally fed rabbits (P<0.001) and from 39.0+/-2.3% to 2.2+/-0.1% in cholesterol-fed rabbits (P<0.001). 6. Ac-YVAD.cmk treatment resulted in a reduction not only of IL-1beta and caspase-1, but also of caspase-3 in the ischaemic myocardium in both normally fed and cholesterol-fed rabbits. 7. No differences in infarct size, the percentage of TUNEL-positive cardiomyocytes, IL-1beta levels or activity of caspase-1 and caspase-3 were observed between Ac-YVAD.cmk-treated normally fed and cholesterol-fed rabbits. 8. This study demonstrates that injection of a selective caspase-1 inhibitor after myocardial ischaemia markedly reduced the detrimental effect conferred by hypercholesterolaemia on myocardial ischaemia-reperfusion injury by attenuating both necrotic as well as apoptotic cell death pathways through inhibition of IL-1beta production and activation of caspase-1 and caspase-3.
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PMID:Attenuation of increased myocardial ischaemia-reperfusion injury conferred by hypercholesterolaemia through pharmacological inhibition of the caspase-1 cascade. 1254 May 17

3-Hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors (statins) are effective in patients with hypercholesterolemia to reduce risk of cardiovascular diseases, because of not only their lowering cholesterol effects but also their pleiotropic effects, such as improvement of endothelial cell dysfunction. On the other hand, statins prevent cell proliferation of various cells, including endothelial cells. We examined effects of all statins available at present on the viability of cultured rat pulmonary vein endothelial cells. Lovastatin, simvastatin, atorvastatin, fluvastatin and cerivastatin, which are hydrophobic statins, markedly reduced cell viability associated with DNA fragmentation, DNA laddering and activation of caspase-3, suggesting apoptotic cell death. Pravastatin, which is a hydrophilic statin, however, did not induce cell apoptosis. Apoptosis induced by hydrophobic statins was associated with activation of apoptosis-related intracellular signal transduction systems; attenuation of localization of RhoA to the membrane, induction of Rac1, and increase in phosphorylation of c-Jun N-terminal kinase and c-Jun. Endothelial cell apoptosis is underlying the improvement of the endothelial dysfunction with hydrophobic statins.
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PMID:All hydrophobic HMG-CoA reductase inhibitors induce apoptotic death in rat pulmonary vein endothelial cells. 1461 3

Evidence has been gathered to suggest that trace amounts of copper induce neurotoxicity by interaction with elevated cholesterol in diet. Copper treatment alone showed no significant learning and memory impairments in behavioral tasks. However, copper-induced neurotoxicity was significantly increased in mice given elevated-cholesterol diet. Trace amounts of copper decreased the activity of SOD and increased the level of malondialdehyde (MDA) in the brain of cholesterol-fed mouse. Copper also caused an increase in amyloid precursor protein (APP) mRNA level and the activation of caspase-3 in the brain of cholesterol-fed mice. The apoptosis-induced nuclear DNA fragmentation was detected in the brain of those mice by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end-labeling staining. These findings suggest that trace amounts of copper induce neurotoxicity in cholesterol-fed mice through apoptosis caused by oxidative stress.
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PMID:Trace amounts of copper induce neurotoxicity in the cholesterol-fed mice through apoptosis. 1713 2

Statins are most commonly prescribed to reduce hypercholesterolemia; however, recent studies have shown that statins have additional benefits, including neuroprotection. Until now, the mechanism underlying statin-induced neuroprotection has been poorly understood. Recent in vivo studies from our lab reported the novel finding that simvastatin increased expression levels of a gene encoding for a major cell survival protein, bcl-2 [Johnson-Anuna et al., J. Pharmacol. Exp. Ther.312 (2005) 786]. The purpose of the present experiments was to determine if simvastatin could protect neurons from excitotoxicity by altering Bcl-2 levels. Neurons were pre-treated with simvastatin and challenged with a compound known to reduce Bcl-2 levels and induce cell death. Simvastatin pre-treatment resulted in a significant reduction in cytotoxicity (lactate dehydrogenase release and caspase 3 activation) following challenge compared with unchallenged neurons. In addition, chronic simvastatin treatment significantly increased Bcl-2 mRNA and protein levels while challenge resulted in a significant reduction in Bcl-2 protein abundance. G3139, an antisense oligonucleotide directed against Bcl-2, abolished the protective effects of simvastatin and eliminated simvastatin-induced up-regulation of Bcl-2 protein. These findings suggest that neuroprotection by simvastatin is dependent on the drug's previously unexplored and important effect of up-regulating Bcl-2.
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PMID:Simvastatin protects neurons from cytotoxicity by up-regulating Bcl-2 mRNA and protein. 1724 Nov 14

Statins are a class of low molecular weight drugs that inhibit the rate-limiting enzyme of the mevalonate pathway 3-hydroxy-3-methylglutaryl-CoA reductase. Statins have been approved and effectively used to control hypercholesterolemia in clinical setting. Recent study showed statin's antitumor activity and suggested a potential role for prevention of human cancers. In this study, we did cell viability, DNA fragmentation, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assays to evaluate the action of statins on prostate cancer cells and used Western blotting and RhoA activation assay to investigate the underlying molecular mechanism of action. Our data showed that lovastatin and simvastatin effectively decreased cell viability in three prostate cancer cell lines (PC3, DU145, and LnCap) by inducing apoptosis and cell growth arrest at G(1) phase. Both lovastatin and simvastatin induced activation of caspase-8, caspase-3, and, to a lesser extent, caspase-9. Both statins suppressed expression of Rb, phosphorylated Rb, cyclin D1, cyclin D3, CDK4, and CDK6, but induced p21 and p27 expression in prostate cancer cells. Furthermore, lovastatin and simvastatin suppressed RhoA activation and c-JUN expression, but not cyclooxygenase-2 expression. Our data showed that the antitumor activity of statins is due to induction of apoptosis and cell growth arrest. The underlying molecular mechanism of statin's action is mediated through inactivation of RhoA, which in turn induces caspase enzymatic activity and/or G(1) cell cycle. Future studies should focus on examining statins and other apoptosis-inducing drugs (e.g., cyclooxygenase-2 inhibitors or curcumin) together to assess their efficacy in prevention of prostate cancer.
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PMID:Statin induces apoptosis and cell growth arrest in prostate cancer cells. 1819 14

Myocardial ischemia-reperfusion (IR) injury occurs frequently in the setting of hypercholesterolemia. We investigated the potential efficacy of a novel thrombin fragment (TP508) on IR injury in a hypercholesterolemic porcine model. Twenty-one hypercholesterolemic male Yucatan pigs underwent 60 min of mid-left anterior descending coronary artery occlusion followed by 120 min of reperfusion. Pigs received either placebo (control, n = 7) or TP508 in two doses (TP508 low dose, n = 7, as bolus of 0.5 mg/kg 50 min into ischemia and an infusion of 1.25 mg.kg(-1).h(-1) during reperfusion period or TP508 high dose, n = 7, a double dose of TP508 low-dose group). Myocardial function was monitored throughout the experiment. The area at risk and myocardial necrosis were determined by Monastryl blue/triphenyl tetrazolium chloride staining. Apoptosis in the ischemic territory was assessed. Coronary microvascular reactivity to endothelium-dependent and -independent factors was measured. Myocardial necrosis was lower in both TP508-treated groups vs. control (P < 0.05). Regional left ventricular function was improved only in the TP508 high-dose group (P < 0.05). Endothelium-dependent coronary microvascular reactivity was greater in both TP508-treated groups (P < 0.05) vs. control. The expression of proteins favoring cell survival, 90-kDa heat shock protein and phospho-Bad (Ser112) was higher in the TP508 high-dose group (P < 0.05). The expression of the cell death signaling proteins, cleaved caspase-3 (P < 0.05), apoptosis-inducing factor (P < 0.05), and poly-ADP ribose polymerase (P = 0.07) was lower in the TP508 low-dose group vs. TP508 high-dose and control. The terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling positive cell count was lower in both TP508 groups compared with the control (P < 0.05). This study demonstrates that, in hypercholesterolemic pigs, TP508 decreases myocardial necrosis and apoptosis after IR. Thus TP508 may offer a novel approach in protecting the myocardium from IR injury.
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PMID:Effect of thrombin fragment (TP508) on myocardial ischemia-reperfusion injury in hypercholesterolemic pigs. 1937 4

We examined the effect of type 2 diabetes on stroke-induced Alzheimer's disease-like pathological and behavioral changes in rats. Rats were treated for 2 months with high fat diet (HFD) followed by streptozotocin (STZ) injection to induce type 2 diabetes (HFD-STZ model). Middle cerebral artery occlusion (MCAO) was used to induce cerebral focal ischemia. Animals were divided into four groups: Sham-NPD, Sham-HFD-STZ, MCAO-NPD and MCAO-HFD-STZ. The results showed that HFD-STZ treatment induced obesity, hypertriglyceridemia, hypercholesterolemia, hyperinsulinemia, hyperglycemia and insulin resistance, characteristics of type 2 diabetes. The performance of rats in the Morris water maze test was impaired in MCAO-NPD and Sham-HFD-STZ rats, indicating cognitive deficits. Hippocampal caspase-3+ and beta amyloid (Abeta+) cell numbers, as well as beta-site amyloid precursor protein-cleaving enzyme (BACE1) levels and activity, increased in both groups. Moreover, HFD-STZ treatment exacerbated stroke-induced cognitive deficits, additively increased MCAO-induced activation of caspase-3, and increased levels of BACE1, C99 and Abeta. However, the level of insulin decreased in MCAO-HFD-STZ rats. These results suggested that type 2 diabetes deteriorated stroke-induced brain damage and cognitive impairment, which might be associated with increased Abeta generation and cytotoxicity. We concluded that type 2 diabetes exacerbated poststroke dementia possibly due to brain injury and synergistic generation of Abeta via activation of BACE1.
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PMID:Exacerbation of poststroke dementia by type 2 diabetes is associated with synergistic increases of beta-secretase activation and beta-amyloid generation in rat brains. 1937 2

Arsenic is an environmental toxicant that reduces the lifespan of circulating erythrocytes during chronic exposure. Our previous studies had indicated involvement of hypercholesterolemia and reactive oxygen species (ROS) in arsenic-induced apoptotic death of erythrocytes. In this study, we have shown an effective recovery from arsenic-induced death signaling in erythrocytes in response to treatment with atorvastatin (ATV) and N-acetyl cysteine (NAC) in rats. Our results emphasized on the importance of cholesterol in the promotion of ROS-mediated Fas signaling in red cells. Arsenic-induced activation of caspase 3 was associated with phosphatidylserine exposure on the cell surface and microvesiculation of erythrocyte membrane. Administration of NAC in combination with ATV, proved to be more effective than either of the drugs alone towards the rectification of arsenic-mediated disorganization of membrane structural integrity, and this could be linked with decreased ROS accumulation through reduced glutathione (GSH) repletion along with cholesterol depletion. Moreover, activation of caspase 3 was capable of promoting aggregation of band 3 with subsequent binding of autologous IgG and opsonization by C3b that led to phagocytosis of the exposed cells by the macrophages. NAC-ATV treatment successfully amended these events and restored lifespan of erythrocytes from the exposed animals almost to the control level. This work helped us to identify intracellular membrane cholesterol enrichment and GSH depletion as the key regulatory points in arsenic-mediated erythrocyte destruction and suggested a therapeutic strategy against Fas-activated cell death related to enhanced cholesterol and accumulation of ROS.
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PMID:Atorvastatin acts synergistically with N-acetyl cysteine to provide therapeutic advantage against Fas-activated erythrocyte apoptosis during chronic arsenic exposure in rats. 2094 10


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