Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Caspases, a family of cysteine proteases, are the key effector proteins of apoptosis. These proteases cleave cellular proteins and are responsible for the destruction of the cell body during apoptosis. They are also involved in the activation of other proteins, such as cytokines. In this study, we demonstrate a novel function for these proteases. Z-Asp-CH2-DCB (Z-Asp), a general caspase inhibitor, blocked cell spreading on collagen-coated plates in a dose-dependent manner but did not affect cell viability. Caspase 3-like activity but not caspase 1-like activity was detected in adherent cells on both collagen-coated and poly-L-lysine-coated plates but not in suspended cells. The caspase 3-like activity was significantly inhibited by Z-Asp. However, only Z-Asp, not specific caspase inhibitors (Z-DEVD for caspase 3, Z-YVAD for caspase 1), was effective in the suppression of cell spreading. The inhibitory effect of Z-Asp was blocked by a phosphokinase C activator, PMA, and a Rho activator, lysophosphatidic acid (LPA), while neither a Rac activator, bradykinin, nor a Cdc42 activator, sphingosine-1 -phosphate, was effective. Immunoprecipitation demonstrated that Z-Asp downregulated the expression of focal adhesion kinase (FAK) protein, downstream of Rho signaling, in adherent cells. Our results suggest that not caspase 1 or 3 but another yet unknown caspase(s) plays an important role in the maintenance of cytoskeleton integrity via FAK protein expression, implying a new function for caspases.
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PMID:Possible involvement of caspase-like family in maintenance of cytoskeleton integrity. 1008 31

The polyphosphoinositides play important roles in transmembrane signalling but are also involved in anchoring cell surface proteins, organellar transport, cytoskeleton organization, and cell survival. The polyphosphoinositides synthesized by phosphatidylinositol-3 kinase (PI-3K), (Ptd(3,4)InsP2, and PtdIns(3,4,5)P3), appear to play a critical role in cell survival by membrane recruitment and activation of Akt kinase. Inhibitors of PI3K, wortmannin, and LY294002, induced a time-dependent activation of caspase-3 (CPP32), with a peak at 6 hr, leading to subsequent cell death by apoptosis in a dorsal root ganglion cell line (F-11). Lowering cyclic AMP (cAMP) levels enhanced both caspase-3 activation and cell death induced by PI3K inhibitors, whereas a nonhydrolyzable cAMP analog (Bt2cAMP), lowered CPP32 and was protective. We stably transfected the F-11 cells with the constitutively active p110 catalytic subunit of PI-3 kinase and observed resistance to both caspase-3 (CPP32) activation and subsequent apoptosis induced by either wortmannin or LY294002. Treatment of F-11 cells with bradykinin (BK) stimulated the hydrolysis of a different polyphosphoinositide, PtdIns(4,5)P2, and enhanced both wortmannin-induced caspase-3 (CPP32) activation and subsequent apoptosis. PtdIns(4,5)P2 is also a precursor of the anti-apoptotic PtdIns(3,4,5) P3 and lowering cAMP levels with opioid agonists for 30 min enhanced both the hydrolysis of PtdIns(4,5) P2 and cellular apoptosis. The enhancement was opioid dose-dependent and opioid antagonist (naloxone)-reversible and was also seen following 24-hr exposure to opioids such as U69,593 and Dala2, Dleu5 enkephalin (DADLE). However, unlike the bradykinin stimulation of PtdIns(4,5)P2 hydrolysis following activation of phospholipase C, the opioid-enhanced hydrolysis was independent of external Ca2+ and was blocked by pertussis toxin, suggesting a different mechanism involving GI, GO, or betagamma-subunits. In summary, both the receptor-mediated lowering of cAMP levels and the hydrolysis of 4,5-polyphosphoinositides have no direct effect on caspase-3 activity or apoptosis but do exacerbate the activation of caspase-3-like activity and subsequent cell death by apoptosis induced by inhibitors of 3-polyphosphoinositide synthesis. We suggest that multiple polyphosphoinositide pathways are involved in the regulation of apoptosis.
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PMID:Multiple polyphosphoinositide pathways regulate apoptotic signalling in a dorsal root ganglion derived cell line. 1065 94

Cardiovascular tissue injury in ischemia/reperfusion has been shown to be prevented by angiotensin-converting enzyme (ACE) inhibitors. However, the mechanism on endothelial cells has not been assessed in detail. Cultured human aortic endothelial cells (HAEC) were exposed to hypoxia with or without reoxygenation. Hypoxia enhanced apoptosis along with the activation of caspase-3. Reoxygenation increased lactate dehydrogenase release time-dependently, along with an increase of intracellular oxygen radicals. ACE inhibitor quinaprilat and bradykinin significantly lessened apoptosis and lactate dehydrogenase release with these effects being diminished by a kinin B2 receptor antagonist and a nitric oxide synthase inhibitor. In conclusion, hypoxia activated the suicide pathway leading to apoptosis of HAEC by enhancing caspase-3 activity, while subsequent reoxygenation induced necrosis by enhancing oxygen radical production. Quinaprilat could ameliorate both apoptosis and necrosis through the upregulation of constitutive endothelial nitric oxide synthase via an increase of bradykinin, with the resulting increase of nitric oxide.
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PMID:Inhibition of angiotensin-converting enzyme protects endothelial cell against hypoxia/reoxygenation injury. 1127 May 6

Vascular endothelial cells play important roles in atherogenesis, and bradykinin is associated with atherosclerosis. The effect of bradykinin on apoptosis in human umbilical vein endothelial cells (HUVECs) was investigated, with a focus on Ca2+ kinetics and nitric oxide production. In serum-free conditions, the number of apoptotic cells increased in a time-dependent manner, but this increase was inhibited by bradykinin in a dose-dependent manner. The apoptosis inhibited by bradykinin was reduced by nitric oxide inhibitor N(G)-monomethyl-L-arginine (L-NMMA) and consequently restored by combined treatment with L-NMMA and L-arginine. Bradykinin increased influx of extracellular Ca2+, generation of inositol 1,4,5-trisphosphate, and release of Ca2+ from intracellular storage sites, thus increasing the total intracellular Ca2+ concentration ([Ca2+]i). Bradykinin increased nitric oxide production, which was inhibited by L-NMMA and restored by combined treatment with L-NMMA and L-arginine. Sodium nitroprusside (SNP) dose-dependently increased nitric oxide production and inhibited apoptosis; however, 10(-5) M SNP did not inhibit apoptosis. Caspase-3 inhibitor, acetyl-Asp-Met-Gln-Asp-aldehyde, enhanced bradykinin-induced inhibition of apoptosis but did not effect bradykinin-induced nitric oxide production. These findings suggest that bradykinin inhibits serum-depletion-induced apoptosis in HUVECs by enhancing nitric oxide production via an increase in [Ca2+]i.
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PMID:Bradykinin inhibits serum-depletion-induced apoptosis of human vascular endothelial cells by inducing nitric oxide via calcium ion kinetics. 1179 Oct 11

The effects of different calcium-mobilizing agents on cell death were characterized in NG108-15 neuroblastoma x glioma hybrid cells. Carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) increased the cytosolic Ca(2+) concentration ([Ca(2+)](i)) and caused cell death. Thapsigargin (TG) not only increased the [Ca(2+)](i) and caused cell death but also induced neurite outgrowth via activation of phospholipase A(2) and cytochrome P450 epoxygenase. In contrast, bradykinin increased the [Ca(2+)](i), but had no effect on cell morphology or cell death. Cell death occurred by two different mechanisms, one of which was caspase-3-dependent and the other caspase-3-independent. Caspase-3 activation was Ca(2+)-dependent, whereas neurite outgrowth was Ca(2+)-independent. TG- or FCCP-induced caspase-3 activation occurred at the same time, but the cell death induced by TG was delayed. TG treatment did not enhance the generation of nitric oxide or cAMP or secretion of glial-derived neurotrophic factor or neurotrophin-3, but activated sphingosine kinase. Furthermore, inhibition of sphingosine kinase accelerated TG-induced cell death, and exogenous sphingosine 1-phosphate (S1P) protected cells from FCCP-induced cell death by about 60%. These results indicate that, in these cells, depletion of intracellular nonmitochondrial or mitochondrial Ca(2+) stores causes cell death, that TG activates phospholipase A(2) and sphingosine kinase, and that arachidonic acid induces neurite outgrowth, whereas S1P delays cell death.
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PMID:Distinct effects of different calcium-mobilizing agents on cell death in NG108-15 neuroblastoma X glioma cells. 1185 28

All small cell (SCLCs) and many non-small cell lung cancers (NSCLCs) have neuroendocrine features including production of neuropeptides and cell surface receptors creating autocrine and paracrine growth loops. Neuropeptides bind to a family of 7-transmembrane receptors and activate heterotrimeric G proteins consisting of G(alphaq) and G(alpha12,13). Substance P derivatives (SPDs) induced apoptosis and inhibited growth of lung cancer cells by discoordinately inhibiting G(alphaq) and stimulating G(alpha12,13). However, these SPDs had low potency and short half-lives. In this report we show that a bradykinin antagonist dimer, CU201, inhibited the growth of SCLC and NSCLC cell lines with or without multidrug-resistant proteins and was 10-fold more potent with a longer plasma half-life than SPDs. Bradykinin agonists in either monomeric or dimeric form and monomeric bradykinin antagonist have no effect on lung cancer cell growth. The dimeric linking moiety of the two molecules was created, requiring a sufficient number of carbon chains to provide critical spacing between the two antagonists. CU201 inhibited intracellular Ca2+ release in response to bradykinin, indicating blockage of the G(alphaq) signal, and stimulated c-Jun kinases, indicating stimulation of the G(alpha12,13) pathway. CU201-induced apoptosis was preceded by unique changes in apparent nuclear DNA binding and by c-Jun kinase and caspase-3 activation. At the concentration at which CU201 inhibited the growth of the cancer cells, it had no effect on the growth of normal lung cells in vitro. CU201 and similar compounds offer hope of becoming a new form of targeted therapy for tumors with neuroendocrine properties.
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PMID:Bradykinin antagonist dimer, CU201, inhibits the growth of human lung cancer cell lines by a "biased agonist" mechanism. 1193 11

Chronically hypoxic rats (exposed to 5000 m elevation for 3 weeks) develop pulmonary hypertension (PH) that is reversed upon return to normoxia and is blocked by bradykinin (BK) antagonist B9430 treatment (100 microg/kg s.c. three times per week). Treatment of rats with both the synthetic VEGF receptor-1/2 antagonist 3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-indolin-2-one (SU5416) (200 mg/kg, single s.c. injection) and hypoxia (3 weeks) causes irreversible severe PH characterized by marked elevation of pulmonary artery pressure (PAP), right ventricular hypertrophy, and obliteration of pulmonary arteries by proliferating endothelial cells (EC). Between weeks I and 2 of treatment, there is increased apoptotic EC death and caspase-3 activity. The combination of hypoxia with VEGFR-1 and -2 blockade appears to cause death of normal lung EC and proliferation of an apoptosis-resistant proliferating EC phenotype. Cotreatment with BK antagonist B9430 and (or) the broad caspase inhibitor Z-Asp-2,6-dichlorobenzoyloxymethylketone (Z-Asp) (2 mg/kg three times per week) prevented development of severe PH and caused significant reduction of PAP: 39.7 +/- 4.6 mmHg in Z-Asp + SU5416, 37.1 +/- 1.2 mmHg in BK antagonist B9430 + SU5416, 27.2 +/- 0.7 mmHg in Z-Asp alone, and 36.6 +/- 3.0 mmHg in BK antagonist alone versus 48 +/- 1.7 mmHg in SU5416-treated rats and 32.8 +/-1.4 mmHg in vehicle-treated controls. The PAP correlated with the right ventricular mass. Pulmonary arteries of rats treated with Z-Asp and BK antagonist B9430 had a marked reduction of intravascular EC, yet there was still evidence of medial muscular hypertrophy, similar to that observed in chronically hypoxic rats not treated with SU5416. We conclude that EC death induced by VEGFR-2 blockade with SU5416 may trigger an EC selection process that allows for the expansion of apoptosis-resistant EC, possibly driven by mechanisms independent of VEGF and VEGFR-2.
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PMID:A bradykinin antagonist and a caspase inhibitor prevent severe pulmonary hypertension in a rat model. 1202 60

Histidine-proline-rich glycoprotein (HPRG) is an abundant multidomain plasma protein evolutionarily related to high-molecular-weight kininogen. The cleaved form of high-molecular-weight kininogen has recently been demonstrated to exhibit antiangiogenic activities in vitro (J. C. Zhang et al., FASEB J., 14: 2589-2600, 2000), mediated primarily through domain 5. HPRG contains a histidine-proline-rich (H/P) domain with sequence and functional similarities to HKa-D5. We hypothesized that HPRG may also have antiangiogenic properties, localized within its H/P domain. The H/P domain is highly conserved among species, and because rabbit H/P domain is more resistant to internal proteolytic cleavage than the human domain, the rabbit HPRG (rbHPRG) was primarily used to assess the antiangiogenic activity of HPRG. Rabbit HPRG inhibited human umbilical vein endothelial cell (HUVEC) tube formation stimulated by fibroblast growth factor-2 (FGF-2) or vascular endothelial growth factor on a Matrigel surface as well as cell proliferation of FGF-2 stimulated HUVECs. The antiangiogenic activity of rbHPRG was localized to the H/P domain by use of proteolytic fragments of rbHPRG and was further confirmed and characterized in two in vivo models of angiogenesis: the chorioallantoic membrane of the chick assay and the mouse Matrigel plug assay. Caspase-3 activation was observed in HUVECs stimulated with FGF-2 in the presence of rbHPRG, suggesting that apoptosis of activated endothelial cells may be one of the mechanisms underlying its antiangiogenic activity. Finally, the H/P domain of rbHPRG reduced tumor cell number when tumor cells were co-inoculated in the Matrigel plug assay. In conclusion, the H/P domain within HPRG induces the apoptosis of activated endothelial cells leading to potent antiangiogenic effects.
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PMID:Histidine-proline-rich glycoprotein has potent antiangiogenic activity mediated through the histidine-proline-rich domain. 1223 5

Plasminogen activator inhibitor-1 (PAI-1) and two-chain high molecular weight kininogen (HKa) exert anti-adhesive properties in vitronectin-dependent cell adhesion. Here, the hypothesis was tested that these anti-adhesive components promote apoptosis in vascular cells. PAI-1 or HKa induced a 2- to 3-fold increase in apoptosis of human umbilical-vein endothelial cells (HUVEC) and vascular smooth muscle cells (VSMC) adherent to vitronectin, as determined by annexin V-FACS assay, similar to alphav-integrin inhibitor cyclo-(Arg-Gly-Asp-D-Phe-Val)-peptide (cRGDfV). Apoptosis occurred after 12 h incubation and was attributable to caspase 3 activation that in turn induced DNA fragmentation. Induction of apoptosis strongly correlated with the anti-adhesive effect of PAI-1 and HKa on these cells. In contrast, PAI-1 and HKa did not affect fibronectin-dependent adhesion or cell survival. uPA did not influence apoptosis in vitronectin- or fibronectin-adherent cells. In atherosclerotic vessel sections, congruent distribution of vitronectin, PAI-1, HK, and of components of the urokinase plasminogen activator/receptor system with apoptotic cells lining foam cell lesions was demonstrated by immunostaining. These results indicate that inhibition of vitronectin-dependent cell adhesion through PAI-1 and HKa correlates with apoptosis induction in vascular cells mediated through the caspase 3 pathway. Co-distribution of apoptosis with plasminogen activation system components in atherosclerosis exemplifies the significance of anti-adhesive mechanisms and apoptosis for tissue remodeling, such as in neointima development.
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PMID:Induction of apoptosis in vascular cells by plasminogen activator inhibitor-1 and high molecular weight kininogen correlates with their anti-adhesive properties. 1271 93

Myocardial ischemia-reperfusion injury involves necrosis and apoptosis. The inhibition of angiotensin-converting enzyme (ACE) has been reported to suppress infarct size. In this study, it was investigated whether an ACE inhibitor affected myocardial apoptosis and apoptosis-related proteins in rats with experimental myocardial infarction. Anesthetized Sprague-Dawley rats were divided into four groups. Group I underwent 30 minutes of left coronary artery occlusion followed by 24 hours of reperfusion (control group); Group II underwent oral administration of the ACE inhibitor quinapril (10 mg/kg/day) before coronary occlusion (quinapril group); Group III underwent administration of the bradykinin B(2)-receptor antagonist Hoe 140 (250 microg/kg/day, subcutaneously) with quinapril (quinapril + Hoe 140 group); and Group IV underwent administration of Hoe 140 alone (Hoe 140 group). After reperfusion, myocardial infarct size was determined by triphenyltetrazolium chloride staining. Myocardial apoptosis was detected immunohistologically using terminal deoxynucleotidyl transferase-mediated nick end labeling staining and DNA electrophoresis. Myocardial caspase-3 activation was analyzed by Western blot and the expressions of Bcl-xL and Bax proteins were detected immunohistochemically. Quinapril significantly reduced the ratio of myocardial infarct size in the ischemic area at risk. In addition, quinapril significantly suppressed the incidence of apoptotic myocytes around the necrotic region (from 18.9 +/- 0.8% to 8.6 +/- 1.0%; P < 0.0001), the intensity of DNA ladder formation, and the activation of caspase-3. Hoe 140 attenuated these protective effects of quinapril. In the immunohistochemical study, Bax and Bcl-xL were expressed in myocytes, and ischemia-reperfusion abolished both proteins in the center region of ischemia. The Bax staining was equally observed among all groups. However, Bcl-xL staining remained in the ischemic area widely after quinapril treatment. In addition, Hoe 140 also depleted this effect of quinapril. These results suggest that inhibition of ACE reduces myocardial infarction and apoptosis via the bradykinin B(2) receptor in part. The antiapoptotic effect of the ACE inhibitor is attributed to the changing expression of Bcl-xL.
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PMID:Effects of ACE inhibition on myocardial apoptosis in an ischemia-reperfusion rat heart model. 1277 65


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