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)

Females have a lower incidence of heart failure and improved survival after myocardial ischemia-reperfusion (I/R) compared with males. Although estrogen-suppressed cardiomyocyte apoptosis may be mediated through the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway, it is unclear whether this action is mediated via estrogen receptor beta (ERbeta). Therefore, we hypothesized that ERbeta mediates estrogen-induced cardioprotection through PI3K/Akt and antiapoptotic signaling in females but not in males. Isolated male and female hearts from ERbeta knockout (ERbetaKO) and wild-type (WT) mice (n = 5 mice/group) were subjected to 20-min ischemia followed by 60-min reperfusion (Langendorff). Ablation of ERbeta significantly decreased postischemic recovery of left ventricular developed pressure in female, but not male, hearts. Reduced activation of PI3K and Akt was noted in female ERbetaKO hearts, which was associated with increased expression of caspase-3 and -8, as well as decreased Bcl-2 levels compared with WT. However, myocardial STAT3, SOCS3 (suppressor of cytokine signaling 3), VEGF, and TNF receptors 1 and 2 levels did not change in ERbetaKO of either sex following I/R. Furthermore, deficiency of ERbeta increased myocardial JNK activation in females but increased ERK1/2 activity in males during acute I/R. We conclude that ERbeta mediates myocardial protection via upregulation of PI3K/Akt activation, decreased caspase-3 and -8, and increased Bcl-2 in female hearts following I/R. These findings provide evidence of ERbeta-mediated PI3K/Akt and antiapoptotic signaling in the myocardium and may lend insight into the mechanistic pathways behind the observed variation in clinical outcomes between males and females after myocardial infarction.
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PMID:Estrogen receptor beta mediates increased activation of PI3K/Akt signaling and improved myocardial function in female hearts following acute ischemia. 1921 25

Stem cell transplantation is a possible therapeutic option to repair ischemic damage to the heart. However, it is faced with a number of challenges including the survival of the transplanted cells in the ischemic region. The present study was designed to use stem cells preconditioned with trimetazidine (1-[2,3,4-trimethoxybenzyl]piperazine; TMZ), a widely used anti-ischemic drug for treating angina in cardiac patients, to increase the rate of their survival after transplantation. Bone marrow-derived rat mesenchymal stem cells (MSCs) were subjected to a simulated host tissue environment by culturing them under hypoxia (2% O(2)) and using hydrogen peroxide (H(2)O(2)) to induce oxidative stress. MSCs were preconditioned with 10 microM TMZ for 6 h followed by treatment with 100 microM H(2)O(2) for 1 h and characterized for their cellular viability and metabolic activity. The preconditioned cells showed a significant protection against H(2)O(2)-induced loss of cellular viability, membrane damage, and oxygen metabolism accompanied by a significant increase in HIF-1alpha, survivin, phosphorylated Akt (pAkt), and Bcl-2 protein levels and Bcl-2 gene expression. The therapeutic efficacy of the TMZ-preconditioned MSCs was evaluated in an in vivo rat model of myocardial infarction induced by permanent ligation of left anterior descending coronary artery. A significant increase in the recovery of myocardial function and up-regulation of pAkt and Bcl-2 levels were observed in hearts transplanted with TMZ-preconditioned cells. This study clearly demonstrated the potential benefits of pharmacological preconditioning of MSCs with TMZ for stem cell therapy for repairing myocardial ischemic damage.
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PMID:Pharmacological preconditioning of mesenchymal stem cells with trimetazidine (1-[2,3,4-trimethoxybenzyl]piperazine) protects hypoxic cells against oxidative stress and enhances recovery of myocardial function in infarcted heart through Bcl-2 expression. 1921 29

Gelsolin, a calcium-regulated actin severing and capping protein, is highly expressed in murine and human hearts after myocardial infarction and is associated with progression of heart failure in humans. The biological role of gelsolin in cardiac remodeling and heart failure progression after injury is not defined. To elucidate the contribution of gelsolin in these processes, we randomly allocated gelsolin knockout mice (GSN(-/-)) and wild-type littermates (GSN(+/+)) to left anterior descending coronary artery ligation or sham surgery. We found that GSN(-/-) mice have a surprisingly lower mortality, markedly reduced hypertrophy, smaller late infarct size, less interstitial fibrosis, and improved cardiac function when compared with GSN(+/+) mice. Gene expression and protein analysis identified significantly lower levels of deoxyribonuclease (DNase) I and reduced nuclear translocation and biological activity of DNase I in GSN(-/-) mice. Absence of gelsolin markedly reduced DNase I-induced apoptosis. The association of hypoxia-inducible factor (HIF)-1alpha with gelsolin and actin filaments cleaved by gelsolin may contribute to the higher activation of DNase. The expression pattern of HIF-1alpha was similar to that of gelsolin, and HIF-1alpha was detected in the gelsolin complex by coprecipitation and HIF-1alpha bound to the promoter of DNase I in both gel-shift and promoter activity assays. Furthermore, the phosphorylation of Akt at Ser473 and expression of Bcl-2 were significantly increased in GSN(-/-) mice, suggesting that gelsolin downregulates prosurvival factors. Our investigation concludes that gelsolin is an important contributor to heart failure progression through novel mechanisms of HIF-1alpha and DNase I activation and downregulation of antiapoptotic survival factors. Gelsolin inhibition may form a novel target for heart failure therapy.
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PMID:Gelsolin regulates cardiac remodeling after myocardial infarction through DNase I-mediated apoptosis. 1935 5

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

Myocardial infarction (MI) stimulates the release of pro-inflammatory substances that induce apoptosis in the limbic system. Pro-inflammatory cytokines are considered as the root cause of apoptosis, although the mechanism is not fully explained and/or understood at this time. In addition, depression may induce gastrointestinal perturbations that maintain the elevated levels of pro-inflammatory cytokines. It has been shown that some specific probiotic formulations may reduce gastrointestinal problems induced by stress and the pro/anti-inflammatory cytokine ratio. Therefore, we hypothesised that probiotics, when given prophylactically, may diminish the apoptosis propensity in the limbic system following a MI. Male adult Sprague-Dawley rats were given probiotics (Lactobacillus helveticus and Bifidobacterium longum in combination) or placebo in their drinking-water for four consecutive weeks. A MI was then induced in the rats by occluding the left anterior coronary artery for 40 min. Rats were killed following a 72 h reperfusion period. Infarct size was not different in the two groups. Bax/Bcl-2 (pro-apoptotic/anti-apoptotic) ratio and caspase-3 (pro-apoptotic) activity were reduced in the amygdala (lateral and medial), as well as in the dentate gyrus in the probiotics group when compared with the placebo. Akt activity (anti-apoptotic) was increased in these same three regions. No significant difference was observed in Ca1 and Ca3 for the different markers measured. In conclusion, the probiotics L. helveticus and B. longum, given in combination as preventive therapy, reduced the predisposition of apoptosis found in different cerebral regions following a MI.
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PMID:Lactobacillus helveticus and Bifidobacterium longum taken in combination reduce the apoptosis propensity in the limbic system after myocardial infarction in a rat model. 1956 93

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

Despite advances in surgical and reperfusion therapy, there is no effective therapy currently exists to prevent the progressive decline in cardiac function following myocardial infarction. Hepatocyte growth factor has potent angiogenic and anti-apoptotic activities. The aim of this study was to investigate the therapeutic effect and dose-effect relationship on postinfarction heart failure with different doses of adenovirus-mediated human hepatocyte growth factor (Ad(5)-HGF) transference in swine models. Totally twenty swine were randomly divided into four groups: (a) control group (null- Ad(5), 1 ml); (b) low-dose group (1 x 10(9) Pfu/ml Ad(5)-HGF, 1 ml); (c) medium-dose group (5 x 10(9) Pfu/ml Ad(5)-HGF, 1 ml); (d) high-dose group (1 x 10(10) Pfu/ml Ad(5)-HGF, 1 ml). Four weeks after left anterior descending coronary artery (LAD) ligation, different doses of Ad(5)-HGF were transferred in three therapeutic groups via right coronary artery. Four and seven weeks after LAD ligation, gate cardiac perfusion imaging was performed to evaluate cardiac perfusion and left ventricular ejection fraction (LVEF). Seven weeks after surgery, the apoptotic index of cardiocyte was observed by TUNEL, the expression of Bcl-2, Bax, alpha-SMA and Factor VIII in the border zones were evaluated by immunohistochemistry, respectively. Four weeks after myocardial infarction, no significant difference was observed among four groups. Three weeks after Ad(5)-HGF transfer, the improvement of cardiac perfusion and LVEF was obviously observed, especially after 1 x 10(10) Pfu Ad(5)-HGF transfer. TUNEL assay showed that 5 x 10(9) Pfu and 1 x 10(10) Pfu Ad(5)-HGF treatment had a obvious reduction in the apoptotic index compared with the null-Ad(5) group, especially after 1 x 10(10) Pfu Ad(5)-HGF treatment. The expression of Bcl-2 protein was increased and the expression of Bax protein was inhibited in the 5 x 10(9) Pfu and 1 x 10(10) Pfu Ad(5)-HGF groups compared with the null-Ad(5) group. The vessel density of Factor VIII(+) and alpha-SMA(+) was increased in Ad(5)-HGF groups compared with the null-Ad(5) group. There were no significant differences in angiogenesis, reducing apoptosis and ameliorating heart function between the 1 x 10(9) Pfu Ad(5)-HGF group and the null-Ad(5) group. Although no statistical difference was observed between 1 x 10(10) Pfu and 5 x 10(9) Pfu Ad(5)-HGF groups, the cardiac protective effects of 1 x 10(10) Pfu Ad(5)-HGF treatment were greater than 5 x 10(9) Pfu Ad(5)-HGF treatment. Different doses of Ad5-HGF injected via noninfarct-related artery could induce angiogenesis, reduce apoptosis and ameliorate heart function, and the cardiac protective effects of 1 x 10(10) Pfu Ad5-HGF is of most significance.
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PMID:Improvement of heart function in postinfarct heart failure swine models after hepatocyte growth factor gene transfer: comparison of low-, medium- and high-dose groups. 1968 Jul 89

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

Clinical studies have indicated that the stent-eluting drugs sirolimus and paclitaxel impact restenosis; however, it is still elusive how these drugs affect the vascular endothelium at the molecular and cellular levels. The purpose of this study was to determine whether sirolimus and paclitaxel induce molecular and cellular alterations in the vascular endothelium. Endothelial regrowth was assessed in human aortic endothelial cells and rat aortic endothelium. Molecular and cellular alterations were analyzed in human aortic endothelial cells by Western blot analysis, transmission electron microscopy, and immunofluorescence staining. Green fluorescent protein-LC3 mice were used to analyze autophagic endothelium. Here, we show that sirolimus and paclitaxel differentially induce self-digesting autophagy in vascular endothelial cells with changes in expression of LC3B, p53, and Bcl-2, considerably suppressing re-endothelialization and revascularization. These results suggest that phenotypic alteration in the endothelium by sirolimus or paclitaxel might affect the rates of late stent thrombosis, myocardial infarction, and mortality.
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PMID:The stent-eluting drugs sirolimus and paclitaxel suppress healing of the endothelium by induction of autophagy. 1981 8

(2E)-2-{6-[(E)-2-carboxyvinyl]-2,3-dihydroxyphenyl}-3-(3,4-dihydroxyphenyl) propenoic acid, a novel compound designated SMND-309, is a new derivate of salvianolic acid B. The present study was designed to investigate the cardioprotective potential of SMND-309 and to elucidate the possible mechanisms on the basis of biochemical, histopathological and immunohistochemical studies in a rat model of acute myocardial infarction induced by permanent ligation of the left coronary artery. The results showed that treatment with SMND-309 via tail vein at doses of 10 and 20 mg/kg significantly prevented the elevation in ST segment level and the increase in serum creatine kinase-MB, lactate dehydrogenase, alanine aminotransferase and cardiac troponin T content. Meanwhile, SMND-309 significantly increased the activities of superoxide dismutase, catalase and glutathione peroxidase, decreased the content of malondialdehyde in myocardium, and reduced the myocardium necrosis scores and the number of apoptosis cardiocytes in accordance with the up-regulated expression of anti-apoptotic protein, Bcl-2 and the down-regulated expression of proapoptotic protein, Bax. Moreover, SMND-309 exhibits significantly higher potency compared to salvianolic acid B at the same mg/kg but not the same mol/kg. These findings indicate that SMND-309 has a protective potential against myocardial infarction injury and the protective effects may be due to its scavenging lipid peroxidation products, increasing endogenous antioxidant defence enzymes and attenuating cardiocyte apoptosis.
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PMID:Cardioprotective effect of SMND-309, a novel derivate of salvianolic acid B on acute myocardial infarction in rats. 1991 62


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