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)

Insulin-like growth factor I (IGF-I) is an important survival growth factor that has been shown to inhibit apoptosis, but the effects of IGF-I on apoptotic signaling remain largely unknown. To investigate IGF-I actions on apoptosis of H9C2 cardiac muscle cells, we have defined the effects of IGF-I on Bcl-2, Bax, caspase 3, DNA fragmentation, and cell survival. The abundance of Bcl-2 and Bax was determined with immunoblotting, and the activities of caspase 3 were assayed with the labeled substrate DEVD-p-nitroanilide. The occurrence of apoptosis was determined by electrophoresis of labeled DNA fragments and by in situ terminal deoxynucleotidyl transferase UTP nick end labeling assay. We found that apoptosis of H9C2 cells, induced by serum withdrawal and doxorubicin, was associated with the induction of Bax and the activation of caspase 3. IGF-I partially inhibited Bax induction, caspase 3 activation, DNA fragmentation, and enhanced cell survival. Interestingly, there is a compensatory rise in the abundance of Bcl-2 upon serum withdrawal and doxorubicin treatment, and IGF-I stimulation resulted in decreased induction of Bcl-2. These results suggest that serum withdrawal- and doxorubicin-induced apoptosis of H9C2 cells probably in part resulted from induction of Bax and caspase 3, and IGF-I inhibited apoptosis by attenuating Bax induction and caspase 3 activation.
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PMID:Insulin-like growth factor I modulates induction of apoptotic signaling in H9C2 cardiac muscle cells. 949 72

Programmed cell death or apoptosis is an active physiological process that permits the removal of unwanted or damaged cells from the body through an intrinsic cell-suicide program. Apoptosis is characterized by condensation of the nucleus and cytoplasm without loss of membrane integrity. The occurrence of apoptosis in the vasculature and myocardium has recently been described. Inappropriate loss of myocardial cells is suggested to contribute to conduction defects and ventricular remodelling after injury. The molecular mechanisms that regulate programmed cell death in cardiac muscle cells are poorly defined. However, recent evidence has suggested that specific genes can either provoke or prevent apoptosis. In this regard, the tumour suppressor protein p53 has been proposed to mediate apoptosis, while the Bcl-2 protein prevents it. Prevention of apoptosis in the heart is potentially of significant therapeutic value given the limited capacity of the heart to repair itself after injury. This study determined that the expression of p53 in ventricular myocytes is sufficient to trigger apoptosis. Moreover, p53 results in a significant increase in the expression of the death-promoting protein Bax. Importantly, the antiapoptotic factor Bcl-2 is sufficient to prevent p53-mediated apoptosis and p53-dependent transcription of Bax in ventricular myocytes. The data substantiate a role for p53 and Bcl-2 as crucial regulators of apoptosis in the heart.
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PMID:Regulators of apoptosis in the heart: a matter of life and death. 955 Oct 35

Apoptosis is regulated by specific intracellular signaling pathways. The development of cardiomyopathy involves the apoptosis of cardiomyocytes; however, the details of their apoptotic signaling are not yet known. Insulin-like growth factor I (IGF I) is an important survival growth factor for myocardium and other tissues, but the effects of IGF I on apoptotic signaling remain largely unknown. To study apoptotic signaling pathways in cardiomyocytes and to understand IGF I actions on the apoptotic signaling of cardiac muscle cells, we have defined the effects of IGF I on Bcl-2, Bax, caspase 3, DNA fragmentation, and cell survival in primary cardiomyocytes. Compared with Bax levels, the levels of Bcl-2 were found to be quite low in these cells. Serum withdrawal and doxorubicin reduced cell viability, increased fragmentation of DNA, increased cellular contents of Bax, and activated caspase 3. IGF I enhanced cell viability, suppressed DNA fragmentation, attenuated Bax induction, and suppressed caspase 3 activation. The levels of Bcl-2-associated Bax were increased after serum withdrawal and incubation with doxorubicin and were reduced by IGF I. Thus, cardiomyocyte apoptosis induced by serum withdrawal and doxorubicin likely results, in part, from the induction of Bax and activation of caspase 3, but IGF I may inhibit cardiomyocyte apoptosis by attenuating Bax induction and caspase 3 activation. These findings provide new insight into the mechanisms of cardiomyocytes apoptosis and may help elucidate how IGF I modulates apoptotic signaling in cardiac muscle.
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PMID:Regulation of cardiomyocyte apoptotic signaling by insulin-like growth factor I. 973 74

The mitochondrial phenotype within cardiac muscle cells is dramatically altered by thyroid hormone. We report here that this can be accounted for, in part, by modifications in the rate of mitochondrial protein import. The import of matrix-localized precursor proteins malate dehydrogenase (MDH) and ornithine carbamoyltransferase was augmented, whereas the insertion of the outer membrane protein Bcl-2 was unaffected by thyroid hormone treatment. Coincident with increases in the import of these matrix-localized precursors were thyroid hormone-induced elevations in the outer membrane receptor Tom20 and the matrix heat-shock protein mthsp70. The phospholipid cardiolipin was not involved in mediating the thyroid hormone-induced increase in import, as judged from adriamycin inhibition studies. When the import reaction was supplemented with rat heart cytosol, we found that 1) MDH import was stimulated, but Bcl-2 import was inhibited and 2) thyroid hormone did not influence the effect of the cytosol on import rates. Thus distinct requirements exist for the mitochondrial import of precursor proteins, destined for different organellar compartments. Although import of these matrix-localized proteins was augmented by thyroid hormone treatment, the proteolysis of matrix proteins was unaffected as indicated by the degradation of cytob2(167)RIC-dihydrofolate reductase, a chimeric protein missorted to the matrix. Thus our data indicate that at least some thyroid hormone-induced modifications of the mitochondrial phenotype occur due to the compartment-specific upregulation of precursor protein import rates, likely mediated via changes in the expression of protein import machinery components.
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PMID:Thyroid hormone modifies mitochondrial phenotype by increasing protein import without altering degradation. 984 12

Although the mechanisms that underlie cardiac cell death remain cryptic, there is emerging evidence that mitochondria may play a pivotal role in this process. The mitochondrion initially deemed the "power house " is now considered to be a central integration site for biological signals that promote cell life or cell death. Since mitochondria contain the necessary apoptotic machinery to activate the cell-death pathway, it is now appreciated that mitochondria play a key decision-making role in whether a cell will live or die following a noxious signal-literally a "license to kill ". Permeability changes to the outer mitochondrial membrane, collapse of membrane potential, permeability pore complex assembly, release of cytotoxic proteins and caspase activation are associated with the mitochondrial-death pathway. Members of the Bcl-2 gene family can promote or suppress cell death by modulating mitochondrial function. Activation of the mitochondrial-death pathway has been reported in several cardiac pathologies and believed to account for the reported apoptosis observed in these disease entities. Given the meager and limited ability of cardiac muscle for repair or self-renewal after injury, the inordinate loss of cardiac cells is considered to be a key underlying factor in ventricular remodeling and decline in ventricular performance in patients with ischemic heart disease or post-myocardial infarction. This review will provide mechanistic insight into the involvement and contribution of the mitochondrion as a regulator of cell death in health and disease with particular focus on the heart.
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PMID:Mitochondria-assisted cell suicide: a license to kill. 1278 72

The development of doxorubicin cardiomyopathy involves apoptosis of cardiac muscle cells. This study was carried out to define the roles of two heat-shock proteins, Hsp10 and Hsp60, on doxorubicin-induced apoptosis in primary cardiomyocytes. Doxorubicin induces apoptosis of cardiomyocytes by activating mitochondria apoptosis signaling. Transducing cardiomyocytes with Hsp10 or Hsp60 with adenoviral vector suppressed the occurrence of apoptosis in the doxorubicin-treated cardiomyocytes. Overexpression of Hsp10 and Hsp60 increased the abundance of the anti-apoptotic Bcl-xl and Bcl-2, and reduced the protein content of the pro-apoptotic Bax. Hsp60 overexpression also significantly reduced doxorubicin induction of Bad, whereas overexpression of Hsp10 did not alter the expression of Bad in the doxorubicin-treated cells. Overexpression of Hsp10 and Hsp60, respectively, stabilized mitochondrial cross-membrane potential, inhibited Caspase 3, and suppressed PARP. These findings indicate that overexpression of Hsp10 and Hsp60 differentially modulated Bcl-2 family and in turn attenuate doxorubicin-induced cardiac muscle death. The effects of Hsp10 and Hsp60 on Bcl-2 family could not be explained by the abundance of Bcl-2 family mRNA levels. Hsp60 interacted with Bcl-xl and Bax in the cardiomyocytes in vivo. The effect of Hsp10 and Hsp60 on the abundance of Bcl-xl could not be blocked by cycloheximide. Moreover, Hsp10 and Hsp60 inhibited ubiquitination of Bcl-xl. These findings suggest that Hsp10 and Hsp60 modulated post-translational modification of Bcl-xl. Antisense Hsp60 reduced the abundance of endogenous Hsp60 in cardiomyocytes and amplified the cytotoxicity of doxorubicin. These data provide a novel link between Hsp10/Hsp60 and cardiac protection in doxorubicin cardiomyopathy.
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PMID:Hsp10 and Hsp60 modulate Bcl-2 family and mitochondria apoptosis signaling induced by doxorubicin in cardiac muscle cells. 1296 36

The clinical use of doxorubicin, a highly active anticancer drug, is limited by its severe cardiotoxic side effects. Increased oxidative stress and apoptosis have been implicated in the cardiotoxicity of doxorubicin. Carvedilol is an adrenergic blocking agent with potent anti-oxidant activity. In this study we investigated whether carvedilol has protective effects against doxorubicin-induced free radical production and apoptosis in cultured cardiac muscle cells, and we compared the effects of carvedilol to atenolol, a beta-blocker with no anti-oxidant activity. Reactive oxygen species (ROS) generation in cultured cardiac muscle cells (H9c2 cells) was evaluated by flow cytometry using dichlorofluorescein (DCF) and hydroethidine (HE). Apoptosis was assessed by measuring annexin V-FITC/propidium iodide double staining, DNA laddering, levels of expression of the pro-apoptotic protein Bax-alpha and the anti-apoptotic protein Bcl-2, and caspase-3 activity. Pre-treatment with carvedilol significantly attenuated the doxorubicin-induced increases in DCF (P < 0.001 compared to cells not pre-treated with carvedilol) and HE (P < 0.01) fluorescence. Doxorubicin increased the fraction of annexin V-FITC-positive fluorescent cells, while pre-treatment with carvedilol reduced the number of positive fluorescent cells (P < 0.01). Doxorubicin-induced DNA fragmentation to a clear ladder pattern, while carvedilol prevented DNA fragmentation. Doxorubicin-induced a fall in mRNA expression of the anti-apoptotic Bcl-2 and an increase in the expression of the pro-apoptotic Bax-alpha. Carvedilol pre-treatment blunted both the decrease of Bcl-2 (P < 0.01) and the increase of Bax-alpha mRNA expression (P < 0.01). Caspase-3 activity significantly increased after the addition of doxorubicin. Concurrently, carvedilol partially inhibited the doxorubicin-induced activation of caspase-3 (P < 0.01). Atenolol did not produce any effect in preventing doxorubicin-induced ROS generation and cardiac apoptosis. Our results suggest that carvedilol is potentially protective against doxorubicin cardiotoxicity by decreasing free radical release and apoptosis in cardiomyocytes.
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PMID:Carvedilol prevents doxorubicin-induced free radical release and apoptosis in cardiomyocytes in vitro. 1538 Jun 72

One of the most compelling issues to impact on contemporary cardiology is arguably the phenomenon of programmed cell death or apoptosis. Studies in the nematode Caenorhabditis elegans provided the first indication that determinants of cell fate crucial for normal worm development were under genetic influences of the ced-3 and ced-9 genes, which promote or prevent cell death, respectively. Extrapolation of these seminal findings led to the discovery of the mammalian ced-3 and ced-9 homologs, which broadly encompass a family of cellular cysteine proteases known collectively as caspases and the Bcl-2 proteins. In quiescent cells, caspases exist as inactive zymogens that are readily activated by autocatalytic processes or by other caspases following a death signal. The caspase-dependent cleavage of intracellular substrates results in the biochemical dismantling of the cell and morphological features characteristic of apoptosis. Recently, a mitochondrial death pathway for apoptosis has been proposed. Perturbations to mitochondria resulting in the loss of mitochondrial membrane potential, DeltaPsim, permeability transition pore (PTP) opening and the release of pro-apoptotic factors by mitochondria including cytochrome c, second mitochondrial activator of caspases/direct IAP binding protein with low pI (Smac/DIABLO), AIF, and others are considered terminal events in the apoptotic pathway. Bcl-2 and related family members are characterized by their ability to promote or prevent cell death. These proteins exert their pro- or anti-apoptosis function by impinging on components of the cell death pathway that underlie caspase activation, mitochondrial dysfunction or both. The limited regenerative potential of the adult cardiac muscle itself, together with the heightened and exciting possibility of regenerating cardiac muscle with cardiac progenitor cells, acknowledges the need for new strategies to suppress and/or prevent inappropriate cardiac cell death in patients with ischemic heart disease or heart failure patients as a therapeutic means of preserving cardiac pump function after injury.
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PMID:Apoptosis of ventricular myocytes: a means to an end. 1562 17

Early heart failure is characterized by elevated plasma Dendroaspis natriuretic peptide-like immunoreactivity (DNP-LI). However, the direct effects of DNP on heart or the heart-associated cell system are not well known. Therefore, we investigated whether DNP induces the apoptosis of H9c2 cardiac muscle cells. H9c2 cardiac muscle cells and rat neonatal cardiomyocytes were treated with various concentrations of DNP. Cell viability and nuclear morphology change were determined by trypan blue staining and Hoechst 33258 staining, respectively. Caspase-3-like activity was measured using specific fluorogenic substrates. Pro-and antiapoptotic proteins were assayed by Western blotting. DNP induced the apoptosis of H9c2 cardiac muscle cells in a dose-dependent manner. Maximum effects occurred at 100 nM concentration of DNP, with a 7-8-fold increase in apoptotic cells, to reach a maximum apoptotic index of 17%. We also identified that H9c2 cardiac muscle cells expressed Natriuretic peptide reactor -A and -B, which respond to DNP to generate cGMP. The treatment with DNP also markedly reduced levels of Bcl-2, inhibitor of apoptosis protein-1, and inhibitor of apoptosis protein-2 and increased the level of Bax and cytochrome c release into cytoplasm and subsequent caspase-3 activation, which co-occurred with increased apoptosis. DNP-induced apoptosis was mediated by cyclic GMP, and this effect was mimicked by dibutylyl-cGMP (30 microM), a membrane permeable analog of cGMP. Furthermore, DNP-induced apoptosis was observed in rat neonatal cardiomyocytes. These results suggest that DNP induces the apoptosis of H9c2 cardiac muscle cells and of cardiomyocytes via cGMP and demonstrate that the operative mechanism includes the regulation of Bcl-2 family proteins.
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PMID:Dendroaspis natriuretic peptide induces the apoptosis of cardiac muscle cells. 1580 58

This study examined the effect of Saeng-Ji-Hwang (SJH: Radix Rehmanniae) on cardiac muscle cells. Adriamycin-exposed H9C2 cardiac muscle cells were treated with a water extract of SJH. The adriamycin induced cell death and caspase-3 activation were significantly inhibited by SJH (2 mg/ml), which can be explained by the increase in Bcl-2 expression and the inhibition of Bax expression. Adriamycin reduced the Mn-SOD protein expression level in H9C2 cardiac muscle cells but a SJH treatment partially but significantly reversed this effect. Manganese (Mn)-TBAP or Mn-TMyM--mitochondria-specific SOD mimetic agent--reduced the adriamycin-induced cytotoxicity. It was also shown that SJH inhibits the release of H2O2 and prevents lipid peroxidation in the presence of adriamycin. This study examined the intracellular GSH level, which showed that adriamycin significantly decreased the intracellular GSH level but SJH increased it. BSO, a selective inhibitor of glutamyl cysteinyl ligase, which is a rate-limiting enzyme in GSH synthesis, did not affect the viability of the cardiac muscle cells. However, a combination of BSO with SJH in the presence of adriamycin reversed the SJH-induced protection. Overall, the results suggest that SJH-associated Mn-SOD and GSH are important factors in the mechanism of the SJH-induced protective mechanism in H9C2 cardiac muscle cells.
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PMID:Saeng-Ji-Hwang has a protective effect on adriamycin-induced cytotoxicity in cardiac muscle cells. 1582 71


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