UNIPROT:P42574 - FACTA Search

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Query: UNIPROT:P42574 (caspase-3)
45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin II (Ang II) importantly contributes to the pathobiology of atherosclerosis. Since endothelial injury is a key event early in the pathogenesis of atherosclerosis, we tested the hypothesis that Ang II may injure endothelial cells by activation of cellular suicide pathways leading to apoptosis. Human umbilical venous endothelial cells (HUVECs) were incubated with increasing doses of Ang II for 18 hours. Apoptosis of HUVECs was measured by ELISA specific for histone-associated DNA fragments and confirmed by DNA laddering and nuclear staining. Ang II dose-dependently induced apoptosis of HUVECs. Simultaneous blockade of both the AT1 and AT2 receptor prevented Ang II-induced apoptosis, whereas each individual receptor blocker alone was not effective. Selective agonistic stimulation of the AT2 receptor also dose-dependently induced apoptosis. Ang II-mediated as well as selective AT2 receptor stimulation-mediated apoptosis was associated with the activation of caspase-3, a central downstream effector of the caspase cascade executing the cell death program. Specific inhibition of caspase-3 activity abrogated Ang II-induced apoptosis. In addition, the NO donors sodium nitroprusside and S-nitrosopenicillamine completely inhibited Ang II-induced apoptosis and eliminated caspase-3 activity. Thus, Ang II induces apoptosis of HUVECs via activation of the caspase cascade, the central downstream effector arm executing the cell death program. NO completely abrogated Ang II-induced apoptosis by interfering with the activation of the caspase cascade.
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PMID:Angiotensin II induces apoptosis of human endothelial cells. Protective effect of nitric oxide. 940 Mar 77

In vitro experiments suggest that angiotensin II (Ang II) may cause growth via angiotensin type 1 (AT(1)) receptors and apoptosis via angiotensin type 2 (AT(2)) receptors. To answer the question of whether AT(1) or AT(2) receptor activation could induce apoptosis in the vasculature in vivo, Wistar rats were infused for 7 days with Ang II (120 ng. kg(-1). min(-1) subcutaneously) and treated with the AT(2) receptor antagonist PD 123319 (30 mg. kg(-1). d(-1) subcutaneously) or the AT(1) receptor antagonist losartan (10 mg. kg(-1). d(-1) orally). Apoptosis in thoracic aorta was quantified by radiolabeled DNA laddering and by terminal deoxynucleotide transferase-mediated dUTP nick end-labeling. The expression of p53, bax, bcl-2, and caspase-3, which play critical roles in apoptotic signaling, was examined by Western blot analysis. The mRNA expression of AT(1) and AT(2) receptors was determined by reverse transcription-polymerase chain reaction. The increase in systolic blood pressure and aortic growth induced by Ang II infusion was completely prevented by losartan alone or losartan given with PD 123319, whereas PD 123319 resulted in a greater increase in systolic blood pressure and aortic growth than Ang II alone. Radiolabeled DNA laddering showed that Ang II infusion+/-losartan or PD 123319 significantly increased apoptosis (147+/-8%, 178+/-20%, and 238+/-41%, respectively, P<0.05 compared with control). Expression of bax and active forms of caspase-3 was increased in the Ang II+PD 123319 group, whereas the expression of p53 and bcl-2 was not significantly different in all groups. The expression of AT(1) and AT(2) receptor mRNA was downregulated by losartan and PD 123319, respectively. Thus, when AT(1) or AT(2) receptors are stimulated in vivo, apoptosis is enhanced in the media of blood vessels. In the case of AT(1) receptor stimulation, this may occur secondary to vascular growth and modulate the latter. Both bax and caspase-3 participate in the pathways of apoptosis triggered by in vivo AT(1) receptor stimulation.
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PMID:In vivo study of AT(1) and AT(2) angiotensin receptors in apoptosis in rat blood vessels. 1052 36

Conventional models of ligand-receptor regulation predict that agonists enhance the tone of signals generated by the receptor in the absence of ligand. Contrary to this paradigm, stimulation of the type 2 (AT(2)) receptor by angiotensin II (Ang II) is not required for induction of apoptosis but the level of receptor protein expression is critical. We compared Ang II-dependent and -independent AT(2) receptor signals involved in regulating apoptosis of cultured fibroblasts, epithelial cells and vascular smooth muscle cells. We found that induction of apoptosis-blocked by pharmacological inhibition of p38 mitogen-activated protein kinase and caspase 3-is a constitutive function of the AT(2) receptor. Biochemical and genetic studies suggest that the level of AT(2) receptor expression is critical for physiological ontogenesis and its expression is restricted postnatally, coinciding with cessation of developmental apoptosis. Re-expression of the AT(2) receptor in remodeling tissues in the adult is linked to control of tissue growth and regeneration. Therefore, we propose that overexpression of the AT(2) receptor itself is a signal for apoptosis that does not require the renin-angiotensin system hormone Ang II.
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PMID:Ligand-independent signals from angiotensin II type 2 receptor induce apoptosis. 1092 83

Previous findings have shown that hypotensive doses of losartan prevent the excess of apoptosis present in the hypertrophied left ventricle of adult spontaneously hypertensive rats (SHR). This study was designed to determine whether angiotensin II facilitates apoptosis in cardiomyocytes of adult SHR. Primary cultures of ventricular cardiomyocytes from 30-week-old normotensive Wistar-Kyoto rats (WKY) and SHR with left ventricular hypertrophy were exposed to 10(-)(9) mol/L angiotensin II for 24 hours. Apoptotic cells were assessed by terminal deoxynucleotidyl transferase assay and confirmed by Annexin V detection. The expression of Bax-alpha, Bcl-2, p53, and caspase-3 proteins was assessed by Western blot assays. The expression of BAX gene was assessed by Northern blot. Angiotensin II increased (P<0.01) cardiomyocyte apoptosis, and this effect was higher (P<0.001) in SHR cells than in WKY cells. Whereas losartan (10(-7) mol/L) blocked the apoptotic effect of the octapeptide in cells from the two strains of rats, PD123319 (10(-7) mol/L) inhibited angiotensin II-mediated apoptosis only in SHR cells. Angiotensin II stimulated (P<0.01) Bax-alpha protein, and this effect was higher (P<0.01) in SHR cells than in WKY cells. Angiotensin II did not modify Bcl-2, p53, and BAX mRNA in cells from the two strains of rats. Angiotensin II induced a similar increase (P<0.05) in the ratio caspase-3/procaspase-3 (an index of caspase-3 activation) in cardiomyocytes from the two strains of rats. The present in vitro results indicate that SHR cardiomyocytes exhibit enhanced susceptibility to angiotensin II-induced apoptosis. Ligand binding to angiotensin II type 1 and type 2 receptors leading to changes in posttranscriptional processing of Bax-alpha and accumulation of this proapoptotic protein may be involved in the abnormal response of SHR cardiomyocytes. These data support a role for angiotensin II in apoptosis observed in the left ventricle of these rats.
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PMID:Mechanisms of increased susceptibility to angiotensin II-induced apoptosis in ventricular cardiomyocytes of spontaneously hypertensive rats. 1111 26

Angiotensin II regulates vascular structure through growth and apoptosis, with implications in pathophysiology. Subtypes of vascular smooth muscle cells with specific morphology, growth, or apoptotic features have been isolated. Here, we investigated the effects of angiotensin II on apoptosis of 2 morphologically different rat aortic smooth muscle cell phenotypes. Spindle and epithelioid cell lines cultured under low serum conditions were stimulated by angiotensin II. Responsiveness was evaluated by calcium signaling. In both phenotypes, an angiotensin II type 1 receptor-mediated transient intracellular calcium peak arose from intracellular pools. However, a sustained nifedipine-sensitive calcium entry occurred specifically in epithelioid cells. Angiotensin II did not impair spindle cell survival, whereas a delayed reduction in cell number occurred in epithelioid cells. Cell death through apoptosis was characterized by cellular and nuclear morphology. Consistently, DNA fragmentation, evaluated by biochemical quantification, nuclei staining, and ladders, and caspase 3-like activity were promoted by angiotensin II in epithelioid cells. Kinetics of annexin V binding showed that apoptosis was a delayed process. Angiotensin II-induced apoptosis of epithelioid cells was prevented by angiotensin II type 1 but not type 2 receptor antagonists and was inhibited by a calcium chelator or calcium antagonist. Conversely, epithelioid cell apoptosis could be induced by a calcium ionophore. Thus, the death signaling promoted by angiotensin II in epithelioid cells involves type 1 receptor-mediated calcium entry. These data suggest that angiotensin II can promote angiotensin II type 1 receptor-mediated apoptosis in vascular smooth muscle cells, depending on their phenotype. This process may play a role in vascular remodeling in cardiovascular diseases.
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PMID:Angiotensin II induces phenotype-dependent apoptosis in vascular smooth muscle cells. 1175 6

Angiotensin II (ANG II) via AT(1) receptors induces apoptosis in cardiomyocytes in vitro. We tested the hypothesis that in vivo AT(1) receptor stimulation is accompanied by cardiac apoptosis and attempted to elucidate the molecular mechanisms involved in the death signaling pathway. Male Sprague-Dawley rats received ANG II (120 ng x kg(-1) x min(-1) sc) for 7 days with or without the AT(1) receptor antagonist losartan (10 mg x kg(-1) x day(-1) orally). Cardiac function was assessed by echocardiography. Apoptosis in the heart was detected and quantified by in situ TdT-mediated dUTP nick-end labeling (TUNEL) and radiolabeled DNA laddering. Expression of bax, bcl-2, caspase 3, and AT(1) and AT(2) receptors was examined by Western blot analysis. Activity of caspase 3 was also measured by a fluorometric immunosorbent enzyme assay. Tail cuff systolic blood pressure was elevated (P < 0.01, n = 6) in ANG II-infused rats (173 +/- 3 mmHg) versus controls (111 +/- 2 mmHg) and reduced by losartan (134 +/- 4 mmHg). Cardiac function was essentially unchanged in ANG II-infused rats. Increased internucleosomal DNA cleavage by TUNEL assay and radiolabeled DNA laddering showed results compatible with enhanced cardiomyocyte apoptosis in the hearts of ANG-II infused rats. The bax-to-bcl-2 ratio, expression of the active form of caspase 3 (17 kDa), and activity of caspase 3 in the hearts of the ANG II group increased more than twofold above controls. Protein expression of AT(1) and AT(2) receptors was significantly increased in ANG II-infused rats compared with control rats. Losartan-treated ANG II-infused rats exhibited normalized apoptosis, bax, caspase 3 activity, and AT(1) receptors. ANG II stimulation of AT(1) receptors in the heart in vivo is associated with an increased rate of apoptosis without major hemodynamic consequences. Bax and caspase 3 are involved in the apoptotic signaling pathway in this experimental paradigm.
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PMID:Effect of AT(1) receptor blockade on cardiac apoptosis in angiotensin II-induced hypertension. 1195 25

Lipopolysaccharide (LPS) from gram-negative bacteria circulates in acute, subacute, and chronic conditions. It was hypothesized that LPS directly induces cardiac apoptosis. In adult rat ventricular myocytes (isolated with depyrogenated digestive enzymes to minimize tolerance), LPS (10 ng/ml) decreased the ratio of Bcl-2 to Bax at 12 h; increased caspase-3 activity at 16 h; and increased annexin V, propidium iodide, and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling staining at 24 h. Apoptosis was blocked by the caspase inhibitor benzyloxycarbonyl-valine-alanine-aspartate fluoromethylketone (Z-VAD-fmk), captopril, and angiotensin II type 1 receptor (AT(1)) inhibitor (losartan), but not by inhibitors of AT(2) receptors (PD-123319), tumor necrosis factor-alpha (TNFRII:Fc), or nitric oxide (N(G)-monomethyl-L-arginine). Angiotensin II (100 nmol/l) induced apoptosis similar to LPS without additive effects. LPS in vivo (1 mg/kg iv) increased apoptosis in left ventricular myocytes for 1-3 days, which dissipated after 1-2 wk. Losartan (23 mg. kg(-1). day(-1) in drinking water for 3 days) blocked LPS-induced in vivo apoptosis. In conclusion, low levels of LPS induce cardiac apoptosis in vitro and in vivo by activating AT(1) receptors in myocytes.
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PMID:Lipopolysaccharide induces apoptosis in adult rat ventricular myocytes via cardiac AT(1) receptors. 1212 89

Despite previous observations on isolated ventricular myocytes, there are still few evidences that angiotensin II induces cardiomyocyte apoptosis in vivo. The possibility that aldosterone, the final hormone of the renin-angiotensin-aldosterone system under Ang II control, can stimulate cardiac apoptosis has not yet been explored. Angiotensin II or aldosterone (1mg/kg each) were infused in adult normotensive rats for different times, and the number of apoptotic ventricular myocyte nuclei was quantified by the TUNEL method, along with caspase-3 activation. The role of angiotensin II type 1 receptor in vivo was assessed by selective blockade with valsartan and ex vivo by binding experiments. In addition, myocytes in primary culture were incubated with Ang II or aldosterone in presence of spironolactone. Continuous infusion of Ang II induced a rapid, AT(1)-mediated increase of apoptotic cardiomyocyte nuclei (from 14+/-9 to 188+/-35 TdT-labeled nuclei/10(6) after 3h, P<0.005) and of activated caspase-3, that normalized after 24h. The normalization was associated with a down-regulation of myocardial AT(1) receptors. Aldosterone stimulated cardiomyocyte apoptosis both in vivo and in isolated cells, to a similar extent as Ang II. The maximal apoptotic rate reported here ( approximately 0.02%) and the transient effect of Ang II suggest that myocyte loss by apoptosis is limited in the present model. The data on aldosterone-induced ventricular myocyte apoptosis deserve further attention to delineate the role of aldosterone in cell death and offer possible mechanistic explanations on the benefits afforded by aldosterone receptor antagonists in heart failure.
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PMID:Appraisal of the role of angiotensin II and aldosterone in ventricular myocyte apoptosis in adult normotensive rat. 1250 63

Loss of cardiomyocytes by apoptosis is proposed to cause heart failure. Angiotensin II (ANG II), an important neurohormonal factor during heart failure, can induce cardiomyocyte apoptosis. Inasmuch as hexarelin has been reported to have protective effects in this process, we examined whether hexarelin can prevent cardiomyocytes from ANG II-induced cell death. Cultured cardiomyocytes from neonatal rats were stimulated with ANG II. Apoptosis was evaluated using fluorescence microscopy, TdT-mediated dUTP nick-end labeling (TUNEL) method, flow cytometry, DNA laddering, and analysis of cell viability by (3,4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). It was found that incubation with 0.1 micromol/l ANG II for 48 h increased cardiomyocyte apoptosis. Administration of 0.1 micromol/l hexarelin significantly decreased this ANG II-induced apoptosis and DNA fragmentation and increased myocyte viability. To further investigate the underlying mechanisms, caspase-3 activity assay and mRNA expression of Bax, Bcl-2, and growth hormone secretagogue receptor (GHS-R; the supposed hexarelin binding site) were examined. GHS-R mRNA was abundantly expressed in cardiomyocytes and was upregulated after administration of hexarelin. These results suggest that hexarelin abates cardiomyocytes from ANG II-induced apoptosis possibly via inhibiting the increased caspase-3 activity and Bax expression induced by ANG II and by increasing the expression of Bcl-2, which is depressed by ANG II. Whether the upregulated expression of GHS-R induced by hexarelin is associated with this antiapoptotic effect deserves further investigation.
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PMID:Hexarelin protects rat cardiomyocytes from angiotensin II-induced apoptosis in vitro. 1461 77

We have recently provided evidence for nicotine-induced complex formation between the alpha7 nicotinic acetylcholine receptor (nAChR) and the tyrosine-phosphorylated enzyme Janus kinase 2 (JAK2) that results in subsequent activation of phosphatidylinositol-3-kinase (PI-3-K) and Akt. Nicotine interaction with the alpha7 nAChR inhibits Abeta (1-42) interaction with the same receptor, and the Abeta (1-42)-induced apoptosis is prevented through nicotine-induced activation of JAK2. These effects can be shown by measuring markers of cytotoxicity, including the cleavage of the nuclear protein poly(ADP-ribose) polymerase (PARP), the induction of caspase 3, or cell viability. In this study, we found that 2-(3-pyridyl)-1-azabicyclo[3.2.2]nonane (TC-1698), a novel alpha7-selective agonist, exerts neuroprotective effects via activation of the JAK2/PI-3K cascade, which can be neutralized through activation of the angiotensin II (Ang II) AT(2) receptor. Vanadate not only augmented the TC-1698-induced tyrosine phosphorylation of JAK2 but also blocked the Ang II neutralization of TC-1698-induced neuroprotection against Abeta (1-42)-induced cleavage of PARP. Furthermore, when SHP-1 was neutralized via antisense transfection, the Ang II inhibition of TC-1698-induced neuroprotection against Abeta (1-42) was prevented. These results support the main hypothesis that states that JAK2 plays a central role in the nicotinic alpha7 receptor-induced activation of the JAK2-PI-3K cascade in PC12 cells, which ultimately contribute to nAChR-mediated neuroprotection. Ang II inhibits this pathway through the AT(2) receptor activation of the protein tyrosine phosphatase SHP-1. This study supports central and opposite roles for JAK2 and SHP-1 in the control of apoptosis and alpha7-mediated neuroprotection in PC12 cells.
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PMID:The neuroprotective effect of 2-(3-pyridyl)-1-azabicyclo[3.2.2]nonane (TC-1698), a novel alpha7 ligand, is prevented through angiotensin II activation of a tyrosine phosphatase. 1472 23

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