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)

Vascular endothelial cell injury or dysfunction has been implicated in the onset and progression of cardiovascular diseases including atherosclerosis. A number of previous studies have demonstrated that the pro-oxidative and pro-inflammatory pathways within vascular endothelium play an important role in the initiation and progression of atherosclerosis. Recent evidence has provided compelling evidence to indicate that interleukin-4 (IL-4) can induce pro-inflammatory environment via oxidative stress-mediated up-regulation of inflammatory mediators such as cytokine, chemokine, and adhesion molecules in vascular endothelial cells. In addition, apoptotic cell death within vascular endothelium has been hypothesized to be involved in the development of atherosclerosis. Emerging evidence has demonstrated that IL-4 can induce apoptosis of human vascular endothelial cells through the caspase-3-dependent pathway, suggesting that IL-4 can increase endothelial cell turnover by accelerated apoptosis, the event which may cause the dysfunction of the vascular endothelium. These studies will have a high probability of revealing new directions that lead to the development of clinical strategies toward the prevention and/or treatment for individuals with inflammatory vascular diseases including atherosclerosis.
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PMID:Role of interleukin-4 in atherosclerosis. 1649 37

Tumor necrosis factor-alpha (TNF-alpha) causes oxidative stress and apoptosis in a variety of cell types. Heme oxygenase (HO) degrades heme to bilirubin, an antioxidant, and carbon monoxide (CO), a cell cycle modulator, and a vasodilator. Newborn pig cerebral microvascular endothelial cells (CMVEC) highly express constitutive HO-2. We investigated the role of HO-2 in protection against TNF-alpha-induced apoptosis in cerebral vascular endothelium. In CMVEC from mice and newborn pigs, 15 ng/ml TNF-alpha alone, or with 10 microg/ml cycloheximide (CHX) caused apoptosis detected by nuclear translocation of p65 NF-kappaB, caspase-3 activation, DNA fragmentation, cell-cell contact destabilization, and cell detachment. TNF-alpha did not induce HO-1 expression in CMVEC. CMVEC from HO-2 knockout mice showed greater sensitivity to apoptosis caused by serum deprivation and TNF-alpha than did wild-type mice. TNF-alpha increased reactive oxygen species generation, including hydrogen peroxide and superoxide radicals, as detected by dihydrorhodamine-123 and dihydroethidium. The TNF-alpha response was inhibited by superoxide dismutase and catalase suggesting apoptosis is oxidative stress related. Inhibition of endogenous HO-2 in newborn pig CMVEC increased oxidative stress and exaggerated apoptosis caused by serum deprivation and TNF-alpha. In HO-1-overexpressing CMVEC (HO-1 selective induction by cobalt portophyrin), TNF-alpha did not cause apoptosis. A CO-releasing compound, CORM-A1, and bilirubin blocked TNF-alpha-induced reactive oxygen species accumulation and apoptosis consistent with the antioxidant and antiapoptotic roles of the end products of HO activity. We conclude that HO-2 is critical for protection of cerebrovascular endothelium against apoptotic changes induced by oxidative stress and cytokine-mediated inflammation.
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PMID:HO-2 provides endogenous protection against oxidative stress and apoptosis caused by TNF-alpha in cerebral vascular endothelial cells. 1682 52

The intense angiogenesis characteristic of early corpus luteum development is dependent upon vascular endothelial growth factor (VEGF) as inhibitors of VEGF administered at the peri-ovulatory period suppress endothelial cell proliferation and progesterone secretion. We now report that administration of VEGF Trap, a soluble decoy receptor-based inhibitor, at the mid- or the late luteal phase in the marmoset results in a rapid decline in plasma progesterone. Since vascularisation of the corpus luteum is largely complete by the mid-luteal phase, it suggested that this functional luteolysis involved mechanisms other than inhibition of angiogenesis. A second experiment investigated the role of VEGF in maintaining the integrity of the luteal vasculature and hormone-producing cells. VEGF Trap was administered to marmosets in the mid-luteal phase and ovaries were obtained 1, 2, 4 or 8 days later for localisation of activated caspase-3 staining in the corpus luteum and compared with those obtained 2, 4 and 8 days after administration of control protein. The number of cells with activated caspase-3 staining was significantly increased after administration of VEGF Trap. Dual staining of activated caspase-3 with the endothelial cell marker CD31 showed that at 1 day post-treatment, more than 90% caspase-3-stained cells were vascular endothelium, prior to detection of an increasing incidence in death of hormone-producing cells on days 2 and 4. Staining with CD31 showed that the endothelial cell area was decreased after treatment. By 8 days after treatment, corpora lutea had regressed to varying degrees, while all control corpora lutea remained healthy. These results show that VEGF inhibition in the mid- or the late luteal phase induces functional luteolysis in the marmoset that is associated with premature and selective death of endothelial cells.
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PMID:Administration of vascular endothelial growth factor Trap during the 'post-angiogenic' period of the luteal phase causes rapid functional luteolysis and selective endothelial cell death in the marmoset. 1700 70

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

Endothelial cell apoptosis is associated with vascular injury and predisposes to atherogenesis. Endothelial cells express anti-apoptotic genes including Bcl-2, Bcl-XL and survivin, which also contribute to angiogenesis and vascular remodeling. We report a central role for protein kinase Cepsilon (PKCepsilon) in the regulation of Bcl-2 expression and cytoprotection of human vascular endothelium against apoptosis. Using myristoylated inhibitory peptides, a predominant role for PKCepsilon in vascular endothelial growth factor-mediated endothelial resistance to apoptosis was revealed. Immunoblotting of endothelial cells infected with an adenovirus expressing a constitutively active form of PKCepsilon (Adv-PKCepsilon-CA) or control Adv-beta-galactosidase demonstrated a 3-fold, PKCepsilon-dependent increase in Bcl-2 expression, with no significant change in Bcl-XL, Bad, Bak, or Bax. The induction of Bcl-2 inhibited apoptosis induced by serum starvation or etoposide, and PKCepsilon activation attenuated etoposide-induced caspase-3 cleavage. The functional role of Bcl-2 was confirmed with Bcl-2 antagonist HA-14-1. Inhibition of phosphoinositide 3-kinase attenuated vascular endothelial growth factor-induced protection against apoptosis, and this was rescued by overexpression of constitutively active PKCepsilon, suggesting PKCepsilon acts downstream of phosphoinositide 3-kinase. Co-immunoprecipitation studies demonstrated a physical interaction between PKCepsilon and Akt, which resulted in formation of a signaling complex, leading to optimal induction of Bcl-2. This study reveals a pivotal role for PKCepsilon in endothelial cell cytoprotection against apoptosis. We demonstrate that PKCepsilon forms a signaling complex and acts co-operatively with Akt to protect human vascular endothelial cells against apoptosis through induction of the anti-apoptotic protein Bcl-2 and inhibition of caspase-3 cleavage.
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PMID:A protein kinase Cepsilon-anti-apoptotic kinase signaling complex protects human vascular endothelial cells against apoptosis through induction of Bcl-2. 1778 60

In diabetes the exposure of the vascular endothelium to high glucose levels results in increased oxidative insult and in vascular dysfunction. We have investigated the effects of rosuvastatin on oxidative stress and apoptosis induced in human umbilical vein endothelial cells (HUVECs) by constant and intermittent high glucose levels. HUVECs were incubated for 14 days in either low (5 mM) or high (20 mM) glucose concentrations, or intermittent high and low glucose on a daily basis. Constant high glucose levels increased p47-phox, p67-phox, and p22-phox expression [components of the Nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidase complex]; endothelial nitric oxide synthase, nitric oxide, and O(2)(-) production; nitrotyrosine, 8-hydroxy-2'-deoxyguanosine, and caspase-3 expression; and reduced Bcl-2 expression. These effects were significantly greater under intermittent compared to constant high/low glucose conditions. The effect of rosuvastatin (1 microM) in the presence or absence of mevalonate (200 microM) was evaluated in the cells under both constant and intermittent glucose conditions. Rosuvastatin almost normalized all these parameters. These effects of rosuvastatin were prevented when mevalonate was also added, demonstrating the link to inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase. These data suggest that rosuvastatin has the potential to prevent damage to and apoptosis of HUVECs induced by high glucose exposure, by reducing oxidative stress. The action of rosuvastatin on antioxidant pathways is related to the inhibition of the overexpression of components of NAD(P)H oxidase induced by the two conditions of high glucose.
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PMID:The protective effect of rosuvastatin in human umbilical endothelial cells exposed to constant or intermittent high glucose. 1819 Oct 76

Statins reduce cardiovascular disease risk and affect endothelial function by cholesterol-dependent and independent mechanisms. Recently, circulating (detached) endothelial cells and endothelial microparticles (EMP) have been associated with endothelial functioning in vitro and in vivo. We investigated whether simvastatin affects endothelial detachment and release of EMP. Human umbilical vein endothelial cells (HUVECs) were incubated with clinically relevant concentrations of simvastatin (1.0 and 5.0 microM), with or without mevalonic acid (100 microM) or geranylgeranylpyrophosphate (GGPP; 20 microM) for 24 hours, and analyzed by flowcytometry and Western blot. Simvastatin at 1.0 and 5.0 microM increased cell detachment from 12.5+/-4.1% to 26.0+/-7.6% (p=0.013) and 28.9 +/- 2.2% (p=0.002) as well as EMP release (p=0.098 and p=0.041, respectively). The majority of detached cells was apoptotic, although the fraction of detached cells that showed signs of apoptosis (>70%) was unaffected by simvastatin. Detached cells and EMP contained caspase 3 and caspase 8, but not caspase 9. Restoring either cholesterol biosynthesis and prenylation (mevalonate) or prenylation alone (GGPP) reversed all simvastatin-induced effects on cell detachment and EMP release. Adherent cells showed no signs of simvastatin-induced apoptosis. Simvastatin promotes detachment and EMP release by inhibiting prenylation, presumably via a caspase 8-dependent mechanism. We hypothesize that by facilitating detachment and EMP release, statins improve the overall condition of the remaining vascular endothelium.
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PMID:Simvastatin-induced endothelial cell detachment and microparticle release are prenylation dependent. 1876 51

Diabetic patients exhibit increased blood plasma levels of methylglyoxal (MG), a metabolite of glucose. Since MG generates advanced glycation end-products (AGEs) that disrupt the functions of such biomolecules as proteins, it is responsible for the progression and complications of diabetes. A functional disorder of the vascular endothelium may also contribute to the progression and complications of diabetes. In endothelial cells, MG is the major precursor for the formation of AGEs. In this study, we examined the effects of MG on vascular endothelial cells and found that it induced the apoptosis of bovine aortic endothelial cells (BAECs). MG induced the collapse of mitochondrial membrane potential, an index of apoptosis, and the elevation of caspase-3 activity, an apoptotic execution enzyme, leading to cell death. Flow cytometric analyses with annexin-V and propidium iodide double staining revealed that cells exposed to a lethal dose of MG displayed features characteristic of apoptosis. MG induced an increase in the level of intracellular reactive oxygen species (ROS) prior to induction of apoptosis. Taken together, these findings suggest that BAECs exposed to MG die by apoptosis due to the increase of intracellular ROS level.
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PMID:[Methylglyoxal-induced apoptosis of endothelial cells]. 1882 64

The oxygen required to meet metabolic needs of all tissues is delivered by the erythrocyte, a small, flexible cell, which, in mammals, is devoid of a nucleus and mitochondria. Despite its simple appearance, this cell has an important role in its own distribution, enabling the delivery of oxygen to precisely meet localized metabolic need. When an erythrocyte enters in a hypoxic area, a signalling pathway is activated within the cell resulting in the release of ATP in amounts adequate to activate purinergic receptors on vascular endothelium, which trigger secretion of nitric oxide and other factors resulting in vasodilatation. Among other mechanisms, binding of deoxyhemoglobin to the cytoplasmic domain of the anion-exchange protein band 3 is probably involved in this pathway. The present study investigates the effect of amyloid beta peptide exposure on this molecular mechanism. We report that deoxygenated human erythrocytes fail to release ATP following 24 h exposure to amyloid beta peptide. Concurrently, amyloid beta peptide induces caspase 3 activation. Preincubation of amyloid beta peptide treated erythrocytes with a specific inhibitor of caspase 3 prevents amyloid-induced caspase 3 activation and restores the erythrocyte's ability to release ATP under deoxygenated conditions. Since the activity of red cell phosphofructokinase, a key step in glycolytic flux, is not modified within the red cell following amyloid peptide exposure, it is likely that ATP release reduction is not dependent on glycolytic flux alterations. It has also been suggested that the heterotrimeric G protein, Gi, and adenylyl cyclase are downstream critical components of the pathway responsible for ATP release. We show that cAMP synthesis and ATP release are not failed in amyloid-peptide-treated erythrocytes in response to incubation with mastoparan 7 or forskolin plus 3-isobutyl-1-methyl xanthine, agents that stimulate cAMP synthesis. In conclusion, these results indicate that amyloid beta peptide inhibits ATP release from deoxygenated erythrocytes by activating red cell caspase 3, suggesting a pathophysiologic role for vascular amyloid peptide in Alzheimer's disease.
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PMID:Amyloid peptide inhibits ATP release from human erythrocytes. 1908 98

20-Hydroxyeicosatetraenoic acid (20-HETE) is an endogenous cytochrome P-450 product present in vascular smooth muscle and uniquely located in the vascular endothelium of pulmonary arteries (PAs). 20-HETE enhances reactive oxygen species (ROS) production of bovine PA endothelial cells (BPAECs) in an NADPH oxidase-dependent manner and is postulated to promote angiogenesis via activation of this pathway in systemic vascular beds. We tested the capacity of 20-HETE or a stable analog of this compound, 20-hydroxy-eicosa-5(Z),14(Z)-dienoic acid, to enhance survival and protect against apoptosis in BPAECs stressed with serum starvation. 20-HETE produced a concentration-dependent increase in numbers of starved BPAECs and increased 5-bromo-2'-deoxyuridine incorporation. Caspase-3 activity, nuclear fragmentation studies, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays supported protection from apoptosis and enhanced survival of starved BPAECs treated with a single application of 20-HETE. Protection from apoptosis depended on intact NADPH oxidase, phosphatidylinositol 3 (PI3)-kinase, and ROS production. 20-HETE-stimulated ROS generation by BPAECs was blocked by inhibition of PI3-kinase or Akt activity. These data suggest 20-HETE-associated protection from apoptosis in BPAECs required activation of PI3-kinase and Akt and generation of ROS. 20-HETE also protected against apoptosis in BPAECs stressed by lipopolysaccharide, and in mouse PAs exposed to hypoxia reoxygenation ex vivo. In summary, 20-HETE may afford a survival advantage to BPAECs through activation of prosurvival PI3-kinase and Akt pathways, NADPH oxidase activation, and NADPH oxidase-derived superoxide.
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PMID:20-HETE increases survival and decreases apoptosis in pulmonary arteries and pulmonary artery endothelial cells. 1913 1


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