Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been reported that programmed cell death (apoptosis) occurs during myocardial infarction. The influence of age on programmed cell death or DNA fragmentation after coronary occlusion has not been extensively characterized. To test the hypothesis that there are age-related differences in susceptibility to DNA fragmentation during ischemia-infarction, we studied DNA fragmentation in young adult and old male F344 rat hearts after acute coronary artery occlusion. Hearts were studied at 1, 3, and 5 h and 1 and 7 days after coronary ligation. The percentage of apoptotic cells was determined by the in situ end-labeling technique, and internucleosomal fragmentation (DNA laddering) pattern was also analyzed. Our results show that 1) DNA fragmentation began earlier and peaked earlier in the old compared with young adult hearts during infarction; 2) there was heightened expression of both Bcl-2 and Bax in the old hearts at baseline; and 3) the Bcl-2-to-Bax ratio was higher in the older heart after coronary ligation. These results suggest that, compared with the young adult heart, the aged heart may be more susceptible to ischemia-induced DNA fragmentation.
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PMID:Bcl-2 and Bax expression in adult rat hearts after coronary occlusion: age-associated differences. 968 94

Na+/H+ exchange (NHE) mediates myocardial ischemic and reperfusion injury. We examined the effects of dietary administration of the potent and selective NHE1 inhibitor cariporide on acute responses to coronary artery ligation and reperfusion in the anesthetized rat. Male Sprague-Dawley rats received control rat chow or an identical diet containing 3 parts per million of cariporide for 1 wk before 225 min of occlusion of the left main coronary artery or 45 min of occlusion followed by 180 min of reperfusion. Hearts were excised and divided into left ventricle, right ventricle, and interventricular septum for analysis of NHE1 mRNA expression and apoptosis by staining with terminal deoxynucleotidyl transferase-mediated nick end labeling. Ischemia and reperfusion were associated with a threefold elevation in NHE1 mRNA expression in control animals that was significantly reduced in cariporide-fed rats. Cariporide reduced mortality from 26% of animals to 0%. The incidence of all arrhythmias was significantly reduced, including ventricular fibrillation (from 42 to 0%) and ventricular tachycardia (from 81 to 15%), as well as the number of ventricular premature beats (from 70 +/- 12 to 17 +/- 6). Cariporide moderately reduced apoptosis only in the reperfused left ventricle to values not significantly greater than those in sham-operated animals, and this was associated with a significantly higher ratio of Bcl-2 to Bax. This study suggests that NHE inhibition with dietary cariporide represents an effective management of acute postinfarction responses.
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PMID:Orally administered NHE1 inhibitor cariporide reduces acute responses to coronary occlusion and reperfusion. 995 Aug 78

Ischemia and reperfusion injure the heart, as manifested by myocardial infarction, postischemic ventricular functional dysfunctions, arrhythmias, and cardiomyocyte apoptosis. Hearts can be adapted to ischemic-reperfusion injury by subjecting them to non-lethal cyclic episodes of short-term ischemia and reperfusion. The adapted myocardium becomes resistant to subsequent lethal ischemic injury. Reactive oxygen species and oxidative stress play crucial roles in the pathophysiology of ischemic-reperfusion injury. The adapted hearts, when subjected to subsequent ischemia and reperfusion, generate a reduced amount of oxygen free radicals compared to the nonadapted hearts. The number of cardiomyocytes undergoing apoptotic cell death is reduced in the adapted hearts subjected to ischemia and reperfusion. In concert, the adapted myocardium is associated with increased antioxidant gene Bcl-2, increased binding activity of the nuclear transcription factor NF kappa B, and reduced binding activity of AP-1 compared to nonadapted hearts. Yet when nonadapted hearts are subjected to ischemia and reperfusion, Bcl-2 is down-regulated while NF kappa B is moderately upregulated and AP-1 is significantly upregulated.
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PMID:Differential regulation of apoptosis by ischemia-reperfusion and ischemic adaptation. 1041 50

Inflammatory mediators of sepsis induce apoptosis in many cell lines. We tested the hypothesis that lipopolysaccharide (LPS) injection in vivo results in induction of early apoptotic and survival pathways as well as evidence of late-stage apoptosis in the heart. Hearts were collected from control rats and at 6, 12, and 24 h after LPS injection (4 mg/kg). Activation of an apoptotic pathway was identified by a 1,000-fold increase in caspase-3 activity at 24 h (P < 0.05). Confirmation of these results occurred when terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining identified myocardial cells undergoing DNA fragmentation with significant levels at 24 h post-LPS injection. LPS also caused early proapoptotic mRNA (Bax) to increase (16% at 24 h, P < 0.05), whereas the Bax protein initially decreased (35% at 6 h, P < 0.05) and then returned to baseline values by 24 h. Six hours after LPS injection, Bcl-2 (early prosurvival) mRNA levels increased, whereas its protein levels decreased (70%, P < 0.05) and then returned to baseline levels by 24 h. Mitochondrial cytochrome c levels decreased, suggestive of mitochondrial involvement. Thus involvement of proapoptotic and prosurvival pathways in the heart occurs during a septic inflammatory response.
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PMID:Endotoxin infusion in rats induces apoptotic and survival pathways in hearts. 1104 37

Two redox-sensitive transcription factors, AP-1 and NF-kappaB, have been implicated in the regulation of apoptosis induced by myocardial ischemia and reperfusion. Hearts adapted to ischemic stress by cyclic episodes of short durations of ischemia and reperfusion attenuate apoptotic cell death. This study was designed to examine the pattern of expression of these transcription factors and the redox sensitive transacting molecule, AP-1, NF-kappaB, and- Bcl-2, during ischemia/ reperfusion and myocardial adaptation to ischemia. NF-kappaB binding activity was low in nonischemic control heart. Fifteen minutes of ischemia resulted in translocation of NF-kappaB from cytosol to nucleus followed by activation. The binding activity of NF-kappaB was further enhanced after 60 min of ischemia. An even higher degree of NF-kappaB binding was noticed in the ischemically adapted myocardium. In contrast, AP-1 binding activity was highest for the hearts subjected to 15 min of ischemia followed by 2 hr of reperfusion. AP-1 binding was higher in the ischemically adapted heart as compared to the control. The Bcl-2 gene, which was found to be present in the control hearts, had lowered expression after 15 min of ischemia and 2 hr of reperfusion. Significant upregulation of Bcl-2 mRNA was noticed in the ischemically adapted hearts. Apoptotic cardiomyocytes were found only in the hearts that were reperfused for at least 90 min. No apoptosis occurred in hearts subjected up to 1 hr of ischemia or ischemic adaptation. Prolonged reperfusion, and not ischemia up to 1 hr, can induce cardiomyocyte apoptosis. In concert, ischemic/reperfusion increases the nuclear binding of both AP-1 and NF-kappaB, but downregulates Bcl-2 gene. Ischemic adaptation attenuates apoptotic cell death, further increases NF-kappaB binding activity and Bcl-2 gene induction, but reduces AP-1 binding activity. These results suggest that AP-1, NF-kappaB, and Bcl-2 are differentially regulated by ischemia/reperfusion and ischemic adaptation.
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PMID:Redox regulation of NF-kappaB and AP-1 in ischemic reperfused heart. 1122 43

The effect of prolonged hypoxia as well as the molecular mechanisms on cardiac cell death is not well established. A possible role of Bcl-2 and Bax in hypoxia-induced apoptosis in different cell types has been proposed. Here we demonstrate the effect of hypoxia on the induction of apoptosis and the expression of Bcl-2-like proteins in vivo and in vitro. Hearts from rats exposed to chronic hypoxia (n = 4) showed an increased rate of apoptosis compared to normoxic hearts (n = 4). The induction of apoptosis in hypoxic hearts correlated with a significant decrease of Bcl-2 protein level, whereas Bax protein expression was increased. Exposure of isolated neonatal rat cardiac myocytes to hypoxia also resulted in a significant increase in apoptosis. However, Bcl-2 and Bax protein levels essentially remained unchanged. Our results may suggest a different molecular mechanism of hypoxia-induced apoptosis in vivo and in vitro.
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PMID:Chronic hypoxia induces apoptosis in cardiac myocytes: a possible role for Bcl-2-like proteins. 1150 55

Left ventricular hypertrophy (LVH) develops very early in experimental renovascular hypertension after clipping of one renal artery and is accompanied by a remodeling of cardiac structure which has not yet been investigated in detail. It was the aim of the present study to analyze changes in cardiomyocyte number and volume in LVH after 2 weeks of renovascular hypertension. Sprague-Dawley rats were subjected to clipping of the left renal artery (2K1C) or sham operation (sham). One group of 2K1C rats received antihypertensive treatment with dihydralazine. The experiment was terminated after 2 weeks. Hearts were investigated using stereological methods, electron microscopy, immunohistology for the proliferation marker proliferating cell nuclear antigen, the pro- and anti-apoptotic proteins Bax and Bcl-2 as well as the TUNEL technique. After 2 weeks, systolic blood pressure and relative left ventricular weight were significantly higher in untreated 2K1C animals than in sham and dihydralazine-treated 2K1C rats. Volume fraction of interstitial tissue and capillary length density were not different, whereas wall thickness of intramyocardial arteries was significantly higher in untreated 2K1C (5.12+/-0.7 micro m) than in sham (3.92+/-0.6 micro m) and in dihydralazine-treated 2K1C (3.91+/-0.7 micro m) rats. Cardiomyocyte diameter and volume were significantly higher in untreated 2K1C than in sham animals. The number of cardiomyocytes per left ventricle was significantly lower in untreated 2K1C rats (5.5+/-1.6 vs 3.9+/-6.9 x10(7)). Using immunohistochemistry, no direct evidence of apoptosis was found, but a relative higher expression of the anti-apoptotic protein bcl-2 expression was seen in untreated 2K1C than in sham animals. This may reflect a protective mechanism as a consequence of earlier occurring apoptosis. These observations document that experimental renovascular hypertension induces a rapidly developing LVH characterized by marked cardiac remodeling and substantial loss of cadiomyocytes.
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PMID:Myocyte loss in early left ventricular hypertrophy of experimental renovascular hypertension. 1268 65

Chronic hypoxia during pregnancy is one of the most common insults to fetal development. We tested the hypothesis that maternal hypoxia induced apoptosis in the hearts of near-term fetal rats. Pregnant rats were divided into two groups, normoxic control and continuous hypoxic exposure (10.5% O2) from day 15 to 21 of gestation. Hearts were isolated from fetal rats of 21-day gestational age. Maternal hypoxia increased hypoxia-inducible factor-1alpha protein in fetal hearts. Chronic hypoxia significantly increased the percentage and size of binucleated myocytes and increased apoptotic cells from 1.4 +/- 0.14% to 2.7 +/- 0.3% in the fetal heart. In addition, the active cleaved form of caspase 3 was significantly increased in the hypoxic heart, which was associated with an increase in caspase 3 activity. There was a significant increase in Fas protein levels in the hypoxic heart. Chronic hypoxia did not change Bax protein levels but significantly decreased Bcl-2 proteins. In addition, chronic hypoxia significantly suppressed expression of heat shock protein 70. However, chronic hypoxia significantly increased expression of the anti-apoptotic protein 14-3-3, among other 14-3-3 isoforms. Chronic hypoxia differentially regulated beta-adrenoreceptor (beta-AR) subtypes with an increase in beta1-AR levels but no changes in beta2-AR. The results demonstrate that maternal hypoxia increases apoptosis in fetal rat heart, which may be mediated by an increase in Fas and a decrease in Bcl-2 proteins. Chronic hypoxia-mediated increase in beta1-AR and decrease in heat shock proteins may also play an important role in apoptosis in the fetal heart.
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PMID:Effect of maternal chronic hypoxic exposure during gestation on apoptosis in fetal rat heart. 1275 58

Recent studies demonstrated that resveratrol, a grape-derived polyphenolic phytoalexin, provides pharmacological preconditioning (PC) of the heart through a NO-dependent mechanism. Because adenosine receptors play a role in PC, we examined whether they play any role in resveratrol PC. Rats were randomly assigned to groups perfused for 15 min with 1) Krebs-Henseleit bicarbonate buffer (KHB) only; 2) KHB containing 10 microM resveratrol; 3) 10 microM resveratrol + 1 microM 8-cyclopentyl-1,3-dimethylxanthine (CPT; adenosine A(1) receptor blocker); 4) 10 microM resveratrol + 1 microM 8-(3-chlorostyryl)caffeine (CSC; adenosine A(2a) receptor blocker); 5) 10 microM resveratrol + 1 microM 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(+/-)-dihydropyridine-3,5-dicarboxylate (MRS-1191; adenosine A(3) receptor blocker); or 6) 10 microM resveratrol + 3 microM 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride [LY-294002, phosphatidylinositol (PI)3-kinase inhibitor], and groups perfused with adenosine receptor blockers alone. Hearts were then subjected to 30-min ischemia followed by 2-h reperfusion. The results demonstrated significant cardioprotection with resveratrol evidenced by improved ventricular recovery and reduced infarct size and cardiomyocyte apoptosis. CPT and MRS 1191, but not CSC, abrogated the cardioprotective abilities of resveratrol, suggesting a role of adenosine A(1) and A(3) receptors in resveratrol PC. Resveratrol induced expression of Bcl-2 and caused its phosphorylation along with phosphorylation of cAMP response element-binding protein (CREB), Akt, and Bad. CPT blocked phosphorylation of Akt and Bad without affecting CREB, whereas MRS 1191 blocked phosphorylation of all compounds, including CREB. LY-294002 partially blocked the cardioprotective abilities of resveratrol. The results indicate that resveratrol preconditions the heart through activation of adenosine A(1) and A(3) receptors, the former transmitting a survival signal through PI3-kinase-Akt-Bcl-2 signaling pathway and the latter protecting the heart through a CREB-dependent Bcl-2 pathway in addition to an Akt-Bcl-2 pathway.
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PMID:Pharmacological preconditioning with resveratrol: role of CREB-dependent Bcl-2 signaling via adenosine A3 receptor activation. 1534 77

The antiapoptotic protein Bcl-2 is targeted to the mitochondria, but it is uncertain whether Bcl-2 affects only myocyte survival after ischemia, or whether it also affects metabolic functions of mitochondria during ischemia. Hearts from mice overexpressing human Bcl-2 and from their wild-type littermates (WT) were subjected to 24 minutes of global ischemia followed by reperfusion. During ischemia, the decrease in pH(i) and the initial rate of decline in ATP were significantly reduced in Bcl-2 hearts compared with WT hearts (P<0.05). The reduced acidification during ischemia was dependent on the activity of mitochondrial F1F0-ATPase. In the presence of oligomycin (Oligo), an F1F0-ATPase inhibitor, the decrease in pH(i) was attenuated in WT hearts, but in Bcl-2 hearts, Oligo had no additional effect on pH(i) during ischemia. Likewise, addition of Oligo to WT hearts slowed the rate of decline in ATP during ischemia to a level similar to that observed in Bcl-2 hearts, but addition of Oligo had no significant effect on the rate of decline in ATP in Bcl-2 hearts during ischemia. These data are consistent with Bcl-2-mediated inhibition of consumption of glycolytic ATP. Furthermore, mitochondria from Bcl-2 hearts have a reduced rate of consumption of ATP on uncoupler addition. This could be accomplished by limiting ATP entry into the mitochondria through the voltage-dependent anion channel, and/or the adenine nucleotide transporter, or by direct inhibition of the F1F0-ATPase. Immunoprecipitation showed greater interaction between Bcl-2 and voltage-dependent anion channel during ischemia. These data indicate that Bcl-2 modulation of metabolism contributes to cardioprotection.
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PMID:Transgenic expression of Bcl-2 modulates energy metabolism, prevents cytosolic acidification during ischemia, and reduces ischemia/reperfusion injury. 1534 51


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