UNIPROT:P10415 - FACTA Search

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)

The p53-upregulated modulator of apoptosis (Puma), a BH3-only member of the Bcl-2 protein family, is required for p53-dependent and -independent forms of apoptosis and has been implicated in the pathomechanism of several diseases, including cancer, acquired immunodeficiency syndrome, and ischemic brain disease. The role of Puma in cardiomyocyte death, however, has not been analyzed. On the basis of the ability of Puma to integrate diverse cell death stimuli, we hypothesized that Puma might be critical for cardiomyocyte death upon ischemia-reperfusion (I/R) of the heart. Here we show that hypoxia-reoxygenation of isolated cardiomyocytes led to an increase in Puma mRNA and protein levels. Moreover, if Puma was delivered by an adenoviral construct, cardiomyocytes died by apoptosis. Under ATP-depleted conditions, however, Puma overexpression primarily induced necrosis, suggesting that Puma is involved in the development of both types of cell death. Consistent with these findings, targeted deletion of Puma in a mouse model attenuated both apoptosis and necrosis. When the Langendorff ex vivo I/R model was used, infarcts were approximately 50% smaller in Puma(-/-) than in wild-type mice. As a result, after I/R, cardiac function was significantly better preserved in Puma(-/-) mice than in their wild-type littermates. Our study thus establishes Puma as an essential mediator of cardiomyocyte death upon I/R injury and offers a novel therapeutic target to limit cell loss in ischemic heart disease.
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PMID:Targeted deletion of Puma attenuates cardiomyocyte death and improves cardiac function during ischemia-reperfusion. 1677 23

Understanding the inflammatory response to myocardial ischemia is an important part of achieving the elusive clinical goal of perfect myocardial protection. While it is established that estrogen affects the chronic inflammatory processes of coronary atherosclerosis, the effects of estrogen on acute myocardial proinflammatory signaling are unknown. To study this, myocardial ischemia and reperfusion was performed in rat hearts from normal adult males, normal adult females, ovariectomized (OVX) females, males supplemented with E2, and OVX females supplemented with E2. Following reperfusion, homogenized hearts were analyzed for TNF-alpha, IL-1beta, and IL-6 gene and protein expression, p38 MAPK activation, and the apoptosis-related proteins caspase-3 and Bcl-2. Hearts from proestrus females demonstrated significantly better post-ischemic functional recovery than males. E2 supplementation to males and OVX females improved post-ischemic myocardial functional recovery, reduced the production of TNF-alpha, IL-1beta and IL-6, and decreased the activation of p38 MAPK and caspase-3 when compared to their untreated counterparts. These results suggest that the effect of estrogen on cardioprotection against myocardial I/R may be attributed to its anti-inflammatory and anti-apoptotic properties. Further understanding of these mechanisms may allow therapeutic manipulation of sex hormones in the treatment of acute ischemic injury.
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PMID:17-beta-Estradiol decreases p38 MAPK-mediated myocardial inflammation and dysfunction following acute ischemia. 1642 50

We tested whether isoflurane preconditioning inhibits cardiomyocyte apoptosis and evaluated the role of the phosphatidylinositol-3-kinase (PI3K)/Akt pathway in anesthetic preconditioning and determined whether PI3K/Akt signaling modulates the expression of pro- and antiapoptotic proteins in anesthetic preconditioning. Six-month-old New Zealand rabbits subjected to 40 min of myocardial ischemia followed by 180 min of reperfusion were assigned to the following groups: ischemia-reperfusion (I/R), isoflurane preconditioning and isoflurane plus PI3K inhibitors, wortmannin and 2-(4-morpholinyl)-8-phenyl-4H-l-benzopyran-4-one (LY294002) (0.6 and 0.3 mg/kg i.v., respectively). Sham-operated, wortmannin+I/R, wortmannin+sham, LY294002+I/R, and LY294002+sham groups were also included. Infarct size was assessed by triphenyltetrazolium chloride staining. Apoptosis was evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and activated caspase-3 assays. Akt phosphorylation, Bax, Bcl-2, Bad, and phosphorylated Bad (phospho-Bad) expression was assessed by immunoblotting. Isoflurane preconditioning reduced infarct size compared with the I/R group: 22+/-4 versus 41+/-5% (p<0.05). The percentage of apoptotic cells decreased in the isoflurane group (3.8+/-1.2%) compared with the I/R group (12.4+/-1.6%; p<0.05). These results were also confirmed by the activated caspase-3 assay. Wortmannin and LY294002 inhibited the effects of isoflurane. Myocardial infarction increased to 44+/-3 and 45+/-2% and the percentage of apoptotic cells was 11.9+/-2.1 and 11.7+/-3.3%, respectively. Akt phosphorylation and Bcl-2 and phospho-Bad expression increased after isoflurane preconditioning, whereas Bax expression decreased. These effects were inhibited by wortmannin and LY294002. The data indicate that isoflurane preconditioning reduces infarct size and myocardial apoptosis after I/R. Activation of PI3K and modulation of the expression of pro- and antiapoptotic proteins may play a role in isoflurane-induced myocardial protection.
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PMID:Volatile anesthetic preconditioning attenuates myocardial apoptosis in rabbits after regional ischemia and reperfusion via Akt signaling and modulation of Bcl-2 family proteins. 1655 37

Sphingomyelin breakdown product ceramide has recently been found to induce an adaptive response and reduce myocardial ischemia/reperfusion injury. Since activation of MAP kinases plays an essential role in myocardial adaptation to ischemic stress and since ceramide is involved in lipid raft formation where MAP kinases can be translocated in response to stress, we reasoned that preconditioning may potentiate the translocation of MAP kinases into the lipid raft. To test the hypothesis, rats were divided into five groups: (i) control, (ii) ischemia/reperfusion (I/R), (iii) I/R+C-2 ceramide, (iv) adapted and (v) adapted+desipramine, an inhibitor of ceramide formation. Isolated hearts were preperfused for 15 min with Krebs Henseleit bicarbonate (KHB) buffer in the absence or presence of 10 microM desipramine followed by adaptation induced by four cyclic episodes of 5 min ischemia and 10 min reperfusion. For myocardial adaptation to ischemia with ceramide, the hearts were perfused with 1 microM C-2 ceramide. All hearts were then subjected to 30 min ischemia and 2 h of reperfusion. As expected, both ischemic adaptation and ceramide adaptation made the heart resistant to I/R injury as evidenced by improved ventricular performance and reduced myocardial infarct size and cardiomyocyte apoptosis, which were significantly blocked with desipramine indicating the involvement of ceramide in ischemic adaptation. Ceramide also participated in the formation of lipid raft, and desipramine disrupted the raft formation. In the adapted hearts, there was an increased association of the proapoptotic p38MAPKalpha with caveolin-1 while there was a reduced association of anti-apoptotic p38MAPKbeta with caveolin-3 indicating reduced amount of p38MAPKalpha and increased amount of p38MAPKbeta were available to the adapted hearts thereby generating a survival signal. Desipramine decreased the association of P38MAPKalpha and C-2 ceramide increased the association of P38MAPKalpha with the lipid raft. The survival signal was further confirmed by increased phosphorylation of AKT and enhanced induction of expression of Bcl-2 during adaptation and its reversal with desipramine. The results indicated a unique ceramide signaling the ischemic and PC hearts involving lipid rafts, which generated a survival signal by differentially associating the p38MAPKalpha and p38MAPKbeta with the caveolin-1 and caveoli-3, respectively.
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PMID:Generation of survival signal by differential interaction of p38MAPKalpha and p38MAPKbeta with caveolin-1 and caveolin-3 in the adapted heart. 1706 50

Ischemic cardiovascular disease is a common age-related disease. The p53-dependent cardiac myocyte apoptosis induced by myocardial ischemia/reperfusion (MI/R) is an important feature in the progression of ischemic heart disease. In the present studies, we hypothesized that inhibition of p53-dependent myocyte apoptosis may improve cardiac dysfunction in aged rats after MI/R. A dose (2.2 mg/kg, i.p.) of pifithrin-alpha (PFT), a p53 inhibitor, or saline was administered to 20-month-old male F344 rats, which were subjected to 30 min of myocardial ischemia by ligating the left main coronary artery, followed by release of the ligature and 4 h of reperfusion. Results of our experiments indicate that MI/R induced a significant decrease in cardiac output index (CI) and mean arterial blood pressure (MABP). Administration of PFT to aged rats 40 min before ischemia significantly improved CI and MABP during 3 to 4 h of reperfusion. The improvement of cardiac function was associated with a marked reduction in DNA fragmentation in the area at risk of the heart when compared with aged MI/R rats pretreated with saline. Interestingly, treatment with PFT 10 min after ischemia or 10 min after reperfusion had a similar protective effect on CI and MABP, but this effect did not reach statistical significance when compared with aged MI/R rats pretreated with saline. Treatment with PFT, however, did not influence plasma creatine kinase activity and the number of circulating leukocytes and infiltrated leukocytes in the area at risk of the heart. Moreover, results of Western blot show that pretreatment with PFT significantly attenuated the ratio of Bax to Bcl-2 in the area-at-risk tissue of the heart compared with that of rats pretreated with saline. Our results suggest that pretreatment with PFT significantly improved cardiac function. The mechanism of protective effect of PFT may involve the inhibition of p53 transcriptional function, thereby attenuating the p53/Bax-mediated myocyte apoptosis during the reperfusion period.
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PMID:Pifithrin-alpha attenuates p53-mediated apoptosis and improves cardiac function in response to myocardial ischemia/reperfusion in aged rats. 1711 37

Opening of the permeability transition pore (PTP) is a key event in ischemia-reperfusion injury and several ligands of the peripheral benzodiazepine receptor (PBR), a mitochondrial outer membrane protein possibly associated with PTP, have been demonstrated as potent cardioprotective agents. Here, we investigated the mechanisms by which the specific PBR ligand 4'-chlorodiazepam (CDZ) protected the myocardium against ischemia-reperfusion. In either global or regional models of myocardial ischemia-reperfusion in rats, CDZ reduced infarct size in a dose-dependent manner (e.g., 11 +/- 1% of the area at risk at 10 mg/kg versus 31 +/- 3% in control; p < 0.05) and to a similar extent as ischemic or diazoxide-induced preconditioning. CDZ (10 mg/kg) reduced apoptosis (terminal deoxynucleotidyl transferase dUTP nick-end labeling staining), restored mitochondrial recovery, improved oxidative phosphorylation parameters, and reduced mitochondrial membrane permeabilization with inhibition of cytochrome c and apoptosis-inducing factor releases. CDZ increased the resistance of mitochondria to Ca2+-induced PTP opening. All these cardioprotective effects of CDZ were associated with an improved stabilization of the association of Bcl-2 with the mitochondrial membrane and inhibition of the association of a cytosolic fragment of Bax, occurring during ischemia-reperfusion, with the outer mitochondrial membrane. In addition, the PTP opener atractyloside (20 microM) and the Bcl-2 inhibitor ethyl-2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (HA14-1) (20 microM) abrogated CDZ-induced reduction of infarct size. These results demonstrate that PBR occupancy by CDZ renders the heart more resistant to ischemia-reperfusion injury by limiting mitochondrial membrane permeabilization. This is due to a reorganization of the balance between pro- and antiapoptotic proteins of the Bcl-2 family proteins at the level of mitochondrial membranes.
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PMID:Peripheral benzodiazepine receptor-induced myocardial protection is mediated by inhibition of mitochondrial membrane permeabilization. 1764 Sep 50

Recently, we have reported that purified Salvia miltiorrhiza extract (PSME) could prevent myocardial infarction in vivo and myocardial ischemia/reperfusion injury in isolated rat hearts (ex vivo). The aim of this project is to determine whether PSME exerts any cardioprotective effects in vitro. The vascular smooth muscle cell line was used and the effects of the drugs were determined after inducing hypoxia. Gene expression levels of the pro-apoptotic genes Asp53, Bax, and Fas were significantly down-regulated by 0.78-, 0.82-, and 0.87-fold, respectively, and Bcl-2 was up-regulated by 0.82-fold in the PSME-treated groups as compared to the hypoxic group (P<0.05). Significant reduction in immunoreactivity of the protein products of these genes as well as least nuclear green fluorescence observed in TUNEL staining indicate the therapeutic potential of this drug. Furthermore, cardiac antioxidant enzymes assay confirmed this deduction as PSME had slight preserving effects on superoxide dismutase and catalase (0.25 +/- 0.01 vs 0.488 +/- 0.02 units/mg protein and 0.026 +/- 0.012 vs 0.076 +/- 0.01 mumol per min per mg protein, respectively; each P<0.05). No significant results were obtained with glutathione S-transferase and GSH peroxidase antioxidant tests. Our results demonstrated that PSME exerts antioxidant effects in vitro, indicating the therapeutic potential of this drug.
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PMID:Effects of purified Salvia miltiorrhiza extract on cardiac vascular smooth muscle hypoxic cells. 1765 8

This study is to investigate if madecassoside can protect against myocardial reperfusion injury in rabbit heart in vivo. The ischemia reperfusion model was established. Left ventricular function and ECG were monitored at the ischemia and reperfusion period. The infarct areas were expressed as percentage. The levels of LDH, CK, MDA and SOD were measured and C-reactive protein (CRP) in serum was measured by ELISA kit. Cardiomyocyte apoptosis were measured by TUNEL staining. A monoclonal rabbit anti-goat Bcl-2 proteins as primary antibody was used for Bcl-2 immunohistochemical staining. Treatment with madecassoside (3.2, 1.6 and 0.8 mg x kg(-1)) i.v. during ischemia reperfusion injury attenuated myocardial damage, that is, characteristic of decreasing infarct size, decreasing LDH and CK release. Activities of SOD were diminished and MDA level increased obviously in control group whereas pretreatment with madecassoside significantly blunted the decrease of SOD activity, markedly reduced the levels of MDA, CRP and cardiomyocyte apoptosis, and upregulated the expression of Bcl-2. Madecassoside has the protective effect against myocardial ischemia reperfusion injury, and effects of anti-lipid peroxidation, enhancement of SOD activity, anti-inflammation and anti-apoptosis.
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PMID:[Protective effect of madecassoside against reperfusion injury after regional ischemia in rabbit heart in vivo]. 1770 67

The aim of this study was to investigate the effects of paeoniflorin (PF) and paeonol (PN), the main active compounds of the Paeonia albiflora Pallas, on myocardial ischemia and reperfusion (I/R)-induced injury in Sprague-Dawley rats IN VIVO. Under anesthesia, the rats were subjected to 25 min of ischemia by ligation of the left anterior descending coronary artery (LAD) followed by 6 h (Western blot analysis) or 24 h (hemodynamics and infarct size) of reperfusion. When the infarct size was measured as the percentage of the area at risk, both PF (25.0 % +/- 7.0 %) and PN (24.1 % +/- 5.5 %) significantly (P < 0.05) reduced it compared to I/R control (54.8 % +/- 2.6 %). Administration of 10 mg/kg PF or PN 1 h prior to I/R injury also resulted in a significant improvement of the hemodynamic parameters. Furthermore, both PF and PN decreased the caspase-3 and Bax expressions but up-regulated Bcl-2 in the left ventricles. The results show that both PF and PN reduced myocardial damage in rat through protection from apoptosis, suggesting that Paeonia albiflora Pallas might be useful in treating myocardial infarction.
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PMID:Paeonol and paeoniflorin, the main active principles of Paeonia albiflora, protect the heart from myocardial ischemia/reperfusion injury in rats. 1820 54

We proposed here that mobilized progenitor cells (MPCs) from the bone marrow are special cell types which carry cytoprotective proteins for cardiac repair following ischemia. Myocardial ischemia was induced by ligation of the left anterior descending coronary artery (LAD) in mice. Progenitor cells in peripheral blood were analyzed by fluorescence-activated cell sorting (FACS). The expression of cytoprotective genes was assayed by ELISA, RT-PCR, and/or real-time PCR. G-CSF was markedly up-regulated in the ischemic myocardium. A good correlation was observed between serum G-CSF and progenitor cells in circulation following LAD ligation. MPCs overexpressed cardiac transcription factor, GATA-4, and anti-apoptotic factor, Bcl-2, besides expression of the surface markers of bone marrow stem cells (BMSCs). Transplantation of cultured MPCs into the ischemic border area significantly improved cardiac function by reducing infarction size. More importantly, MPCs significantly protected cardiomyocytes against apoptosis when co-cultured with cardiomyocytes. The cardiac protection by MPCs was blocked by Bcl-2 neutralizing antibody and GATA-4 siRNA. In contrast, transfection of BMSCs with GATA-4 provided increased protection of myocytes against apoptosis. It is concluded that MPCs are highly cytoprotective and carry protective genes responsible for cardiac repair.
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PMID:Mobilized bone marrow progenitor cells serve as donors of cytoprotective genes for cardiac repair. 1822 54

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