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)

We investigated pharmacological effects of rutin isolated form Lonicera japonica on H2O2-induced cell death in H9c2 cells in vitro and rat myocardial ischemia-reperfusion injury model in vivo. Western blot analysis showed that H2O2 increased expression of cleaved form of caspase-3 and proapoptotic Bax protein, but decreased antiapoptotic Bcl-2 protein in H9c2 cell. However, treatment with rutin decreased expression of both cleaved from of caspase-3 and increased Bcl-2/Bax ratio in H9c2 cells. The protective effect of rutin was inhibited not by JNK inhibitor or p38 MAPK inhibitor but by PI3K inhibitor or ERK inhibitor. Rutin increased phosphorylation of ERK and Akt in H9c2 cells. These anti-apoptotic effects of rutin were confirmed both by annexin-V and TUNEL assay. Furthermore, rutin improved I/R-induced myocardial contractile function and reduced infarct size. Rutin administration also inhibited apoptosis in myocardial tissues in I/R rats by increasing Bcl-2/bax ratio and decreasing active caspase-3 expression. These results suggest that rutin reduced oxidative stress-mediated myocardial damage in vitro model and in vivo model, which might be useful in treatment of myocardial infarction.
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PMID:Rutin from Lonicera japonica inhibits myocardial ischemia/reperfusion-induced apoptosis in vivo and protects H9c2 cells against hydrogen peroxide-mediated injury via ERK1/2 and PI3K/Akt signals in vitro. 1936 15

We examined our hypothesis that (S)-1-(alpha-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (CKD712) inhibits apoptosis in myocardial ischemia and reperfusion (I/R) injury in vivo via activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and by reducing inflammation during I/R. To do this, we induced a 30-min period of ischemia by occlusion of the left anterior descending coronary artery of the rat followed by a 2-h (for phosphorylation of Akt), 6-h (for biochemical analysis), or 24-h (for functional analysis) period of reperfusion to determine the effect of CKD712 treatment. Pretreatment with CKD712 significantly improved myocardial function as evidenced by an increase in the +/-dP/dt and a decrease in the infarct size, which were antagonized by a PI3K inhibitor, wortmannin (WT). Interestingly, CKD712 increased the phosphorylation of Akt and cAMP-response element-binding protein and increased the expression of the Bcl-2 gene, but it reduced the expression of the Bax gene. CKD712 decreased not only the expression but also the activity of the caspase-3 protein in the myocardium after reperfusion. Thus, all of the antiapoptotic effects of CKD712 were significantly inhibited by WT. Furthermore, the antiapoptotic effects of CKD712 and its inhibition by WT in myocardium after reperfusion were confirmed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining. Finally, CKD712 was found to reduce the serum levels of the high-mobility group box 1 protein, tumor necrosis factor-alpha, and the cardiac troponin I protein in addition to tissue levels of malondialdehyde and myeloperoxidase activity in I/R hearts. Taken together, both the activation of PI3K/Akt and its anti-inflammatory action prevent apoptosis in myocardial I/R injury by CKD712.
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PMID:(S)-1-(alpha-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (CKD712) reduces rat myocardial apoptosis against ischemia and reperfusion injury by activation of phosphatidylinositol 3-kinase/Akt signaling and anti-inflammatory action in vivo. 1945 86

Echinocystic acid (EA), a pentacyclic triterpene, was isolated and identified from the fruits of Gleditsia sinensis Lam. The protective effects of EA were evaluated in rat models with acute myocardial ischemia induced by isoproterenol and vasopressin. In the electrocardiogram of anesthetized rats, EA prevented the ST-segment depression induced by isoproterenol or vasopressin in a dose-dependently manner. Furthermore, the mRNA expression of Bcl-2 was analyzed by RT-PCR. EA shows an elevation of Bcl-2 mRNA level in infarcted tissue induced by isoproterenol in rats. These results demonstrated for the first time EA has a cardioprotective effect and may be a natural drug.
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PMID:Protective effects of echinocystic acid isolated from Gleditsia sinensis Lam. against acute myocardial ischemia. 1957 79

The purpose of this study was to assess the short- and long-term cardioprotective effects of darbepoetin-alpha (DA) in a rat myocardial ischemia and reperfusion model and to investigate the signaling pathway through which DA limits cardiomyocytes apoptosis. Rats were subjected to 40 minutes of coronary artery ligation followed by 72 hours or 4 weeks reperfusion and received either DA (3 or 30 microg/kg, DA3 and D30 groups) or vehicle (control) prior to ischemia. In the DA groups reperfused for 72 hours, left ventricular shortening fraction and left ventricular ejection fraction were higher than that in the control rats (P < 0.05), in agreement with a smaller left ventricular (LV) infarct size. DA treatment activated the JAK2/Akt signaling pathway, lowered cleaved caspase-3, and increased both phosphorylated-Bad and phosphorylated-GSK-3beta proteins. This was consistent with the decrease of reactive oxygen species production and the lowered binding of Bad to Bcl-xL and Bcl-2 in a DA30 group of rats. Similarly, in the DA-4-week group, LV function was greater compared to the control. Histology alterations implicated lower LV cardiac fibrosis and greater capillary density; furthermore, both Bcl-xL and Bcl-2 were upregulated. In conclusion, DA afforded short- and long-term cardioprotective effects. Antiapoptotic effects, through the activation of Akt that regulates the Bcl-2 family proteins and activates GSK-3beta, are central in the DA cardioprotective mechanism.
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PMID:Short- and long-term cardioprotective effect of darbepoetin-alpha: role of Bcl-2 family proteins. 1959 69

Interleukin 6 (IL-6) is a pleiotropic cytokine that is highly expressed in response to ischemia and reperfusion. It has dichotomous roles in the heart, functioning both as an inflammatory mediator as well as a protective agent. The aim of this study was to evaluate the effect of IL-6 deficiency on the expression of apoptotic regulatory proteins under both baseline conditions and following induction of ischemia and reperfusion in the mouse heart. C57BL/6J IL-6-/-(TMKopf) (IL6KO) and C57BL/6J mice (WT) were subjected to 30 minutes of local reversible myocardial ischemia in vivo or a sham operation. The expression of Bcl-2, Bax and STAT3 in the heart was assessed by western blotting. Under both baseline conditions and following the sham operation, IL-6 deficiency was associated with reduced expression of Bcl-2 and Bax. The TUNEL-FITC, Evans blue and tetrazolium chloride staining of the hearts following ischemia and reperfusion revealed similar injury in operated IL6KO and WT animals. There was increased STAT3 phosphorylation in operated mice regardless of the genotype. Bcl-2 and Bax expression was also comparable between the mouse strains following ischemia and reperfusion. In summary, these results indicated that IL-6 deficiency affected the basal expression of apoptotic regulators, but this did not profoundly alter the extent of reperfusion injury or apoptosis in the mouse heart following ischemia and reperfusion.
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PMID:Effect of interleukin 6 deficiency on the expression of Bcl-2 and Bax in the murine heart. 1960 50

Intermedin (IMD) is a novel member of the calcitonin/calcitonin gene-related peptide family. We investigated the cardioprotective mechanism of IMD(1-53) in the in vivo rat model of myocardial ischemia/reperfusion (I/R) injury and in vitro primary neonatal cardiomyocyte model of hypoxia/reoxygenation (H/R). Myocardial infarct size was measured by 2,3,5-triphenyl tetrazolium chloride staining. Cardiomyocyte viability was determined by trypan blue staining, cell injury by lactate dehydrogenase (LDH) leakage, and cardiomyocyte apoptosis by terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labeling assay, Hoechst staining, gel electrophoresis and caspase 3 activity. The translocation of mitochondrial cytochrome c of myocardia and expression of apoptosis-related factors Bcl-2 and Bax, phosphorylated Akt and phosphorylated GSK-3beta were determined by western blot analysis. IMD(1-53) (20 nmol/kg) limited the myocardial infarct size in rats with I/R; the infarct size was decreased by 54%, the apoptotic index by 30%, and caspase 3 activity by 32%; and the translocation of cytochrome c from mitochondria to cytosol was attenuated. IMD(1-53) increased the mRNA and protein expression of Bcl-2 and ratio of Bcl-2 to Bax by 81 and 261%, respectively. IMD(1-53) (1 x 10(-7) mol/L) inhibited the H/R effect in cardiomyocytes by reducing cell death by 43% and LDH leakage by 16%; diminishing cellular apoptosis; decreasing caspase 3 activity by 50%; and increasing the phosphorylated Akt and GSK-3beta by 41 and 90%, respectively. The cytoprotection of IMD(1-53) was abolished with LY294002, a PI3K inhibitor. In conclusion, IMD(1-53) exerts cardioprotective effect against myocardial I/R injury through the activation of the Akt/GSK-3beta signaling pathway to inhibit mitochondria-mediated myocardial apoptosis.
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PMID:Activation of Akt/GSK-3beta signaling pathway is involved in intermedin(1-53) protection against myocardial apoptosis induced by ischemia/reperfusion. 1963 12

B-type natriuretic peptide (BNP) is one peptide hormone released in response to myocyte stretch, whose functions play significant roles in health and disease. Its physiologic effects result in improved loading conditions and have led to the development of recombinant BNP as a therapeutic agent for heart failure. Previous work has identified that BNP protect myocardium against reperfusion injury through mitochondrial pathway. Mitochondria are both essential effectors of cardioprotection and primary targets of cardioprotective signaling. Their role during reperfusion is particularly critical because of the conditions that promote both apoptosis by the mitochondrial pathway and necrosis by irreversible damage to mitochondria in association with mitochondrial permeability transition pores (mPTP). After an episode of myocardial ischemia, opening of mPTP, at the onset of reperfusion, is a critical determinant of myocyte death. The relationship of BNP and mPTP in mediating reperfusion-induced cardiomyocytes injury is a novel investigative area. In this study, our results indicated that the beneficial effect of BNP in cultured cardiomyocytes subjected to reperfusion is associated with attenuation of mPTP opening, resultant mitochondrial dysfunction and apoptosis. Further investigation of underlying mechanisms revealed that these were associated with BNP-mediated repolarization of mitochondrial membrane potential (Deltapsi(m)), inhibition of reactive oxygen species (ROS) generation, improvement of Bcl-2 level, and inhibition of Bax and second mitochondria-derived activator of caspases/direct inhibitor of apoptosis protein-binding protein with a low isoelectric point (Smac/DIABLO) levels. In summary, we demonstrate that BNP exerts protective actions within reperfusion by inhibiting mPTP opening and these roles of BNP may involve phosphatidylinositol 3-kinase (PI3K) dependent pathway.
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PMID:B-type natriuretic peptide-induced cardioprotection against reperfusion is associated with attenuation of mitochondrial permeability transition. 1972 Dec 30

Intermedin (IMD) is a novel member of the calcitonin/calcitonin gene-related peptide family. We investigated the cardioprotective mechanism of IMD(1-53) in the in vivo rat model of myocardial ischemia/reperfusion (I/R) injury and in vitro primary neonatal cardiomyocyte model of hypoxia/reoxygenation (H/R). Myocardial infarct size was measured by 2,3,5-triphenyl tetrazolium chloride staining. Cardiomyocyte viability was determined by trypan blue staining, cell injury by lactate dehydrogenase (LDH) leakage, and cardiomyocyte apoptosis by terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labeling assay, Hoechst staining, gel electrophoresis and caspase 3 activity. The translocation of mitochondrial cytochrome c of myocardia and expression of apoptosis-related factors Bcl-2 and Bax, phosphorylated Akt and phosphorylated GSK-3beta were determined by western blot analysis. IMD(1-53) (20 nmol/kg) limited the myocardial infarct size in rats with I/R; the infarct size was decreased by 54%, the apoptotic index by 30%, and caspase 3 activity by 32%; and the translocation of cytochrome c from mitochondria to cytosol was attenuated. IMD(1-53) increased the mRNA and protein expression of Bcl-2 and ratio of Bcl-2 to Bax by 81 and 261%, respectively. IMD(1-53) (1 x 10(-7) mol/L) inhibited the H/R effect in cardiomyocytes by reducing cell death by 43% and LDH leakage by 16%; diminishing cellular apoptosis; decreasing caspase 3 activity by 50%; and increasing the phosphorylated Akt and GSK-3beta by 41 and 90%, respectively. The cytoprotection of IMD(1-53) was abolished with LY294002, a PI3K inhibitor. In conclusion, IMD(1-53) exerts cardioprotective effect against myocardial I/R injury through the activation of the Akt/GSK-3beta signaling pathway to inhibit mitochondria-mediated myocardial apoptosis.
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PMID:Activation of Akt/GSK-3beta signaling pathway is involved in intermedin(1-53) protection against myocardial apoptosis induced by ischemia/reperfusion. 1975 65

The therapy for acute myocardial infarction (AMI) has been improved; yet, AMI remains a major cause of death and heart failure in industrialized countries. B-type natriuretic peptide (BNP), a hormone secreted from the heart, has been shown cardioprotective effects during myocardial ischemia/reperfusion. In the present study, we aimed to examine whether BNP could inhibit myocardial apoptosis during ischemia/reperfusion. Rabbits were randomly divided into three groups (12 animals for each group): sham-operated control and ischemia-reperfusion animals with or without BNP treatment. Occlusion of the left circumflex coronary for 45 min was followed by 3-h reperfusion with infusion of physiological saline (untreated group) or BNP (treated group) starting 5 min before reperfusion and throughout the whole reperfusion. The infarct size, measured by triphenyltetrazolium chloride staining, was reduced by 44% with BNP treatment (P < 0.01). Accordingly, serum levels of creatine kinase and lactate dehydrogenase were markedly reduced in BNP-treated group (P < 0.05) compared with the untreated group. BNP significantly attenuated apoptotic cells (TUNEL-positive cardiomyocyte nuclei) in the myocardium (P < 0.01). The BNP-mediated attenuation of apoptosis was associated with the increased expression of an anti-apoptotic protein Bcl-2 and the reduced expression of a pro-apoptotic protein Bax. Moreover, BNP treatment significantly decreased the magnitude of caspase-3 activation caused by myocardial ischemia-reperfusion. In conclusion, pretreatment with BNP shortly before the onset of reperfusion not only reduces necrosis, but also attenuates myocardial apoptosis. BNP appears to be an ideal pharmacological agent applied as an adjuvant therapy to current myocardial reperfusion strategies.
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PMID:Pretreatment with B-type natriuretic peptide protects the heart from ischemia-reperfusion injury by inhibiting myocardial apoptosis. 1977 27

The involvement of connexins in regulating cell growth and death has recently been reported. We have investigated whether Cx43 (connexin43) contributes to MSC (mesenchymal stem cell) survival and improves therapeutic efficacy in MI (myocardial infarction). Genetically modified Cx43 MSCs were exposed to hypoxic conditions or injected intramyocardially into a rat MI model. MSCs overexpressing Cx43, with more Bcl-2 and phosphorylated Akt, but less Bax, were relatively tolerant to hypoxic injury. After transplantation, this Cx43 overexpression enhanced cell survival and reduced infarct size, improving contractile performance. Cx43 inhibition by SiRNA reversed the effects of Cx43 overexpression. Therefore, Cx43 may act as a potential target for improving the therapeutic efficacy of MSCs in ischaemic heart disease.
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PMID:Connexin43 promotes survival of mesenchymal stem cells in ischaemic heart. 2006 45


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