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)

Cardiomyocyte (CM) apoptosis has been reported in a variety of cardiovascular diseases, including myocardial infarction, ischemia/reperfusion, end-stage heart failure, arrhythmogenic right ventricular dysplasia, and adriamycin-induced cardiomyopathy. The role of CM apoptosis in the development and progression of cardiac diseases merits further investigation. Cumulative evidence suggests that reactive oxygen species (ROS), which have been implicated in cardiac pathophysiology, can trigger myocyte apoptosis by up-regulating proapoptotic proteins, such as Bax and caspases, and the mitochondria-dependent pathway. These apoptotic proteins and pathways are inhibited by various antioxidants, as well as by overexpression of the antiapoptotic protein Bcl-2 by way of the antioxidant pathway. Detection of CM apoptosis with the terminal transferase-mediated DNA nick-end labeling assay alone has recently been questioned because of technical concerns regarding its sensitivity and specificity. Because CMs are mononuclear or binuclear, if only one nucleus or a certain percentage of fragmented nuclei is stained with TUNEL assay at the early stage of apoptotic cell death, it remains unknown whether this particular early apoptotic CM is still functionally active. The issue of TUNEL specificity further questions reports of high percentages of apoptotic CM nuclei (0.02%-35%) in the heart. Nevertheless, oxidative stress is a major apoptotic stimulus in many cardiovascular diseases and the process can be inhibited by antioxidants both in vitro and in vivo.
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PMID:Apoptosis and oxidants in the heart. 1464 32

Nicorandil has been shown to induce an infarct-limiting effect similar to that induced by the early phase of ischemic preconditioning (PC). The goals of this study were to determine whether nicorandil induces a delayed cardioprotection that is analogous to the late phase of ischemic PC and, if so, whether nicorandil-induced late PC is associated with upregulation of cardioprotective proteins. Chronically instrumented, conscious rabbits received vehicle (intravenous normal saline; control group, n = 10), nicorandil (100 microg/kg bolus + 30 microg x kg(-1) x min(-1) i.v. for 60 min; nicorandil group, n = 10), or ischemic PC (6 cycles of 4-min coronary occlusion/4-min reperfusion; PC group, n = 8). Twenty-four hours later, rabbits underwent a 30-min coronary occlusion, followed by 3 days of reperfusion. Myocardial infarct size was significantly reduced in rabbits pretreated with nicorandil (27.5 +/- 5.3% of the risk region) or with ischemia (30.3 +/- 4.2%) versus controls (59.1 +/- 4.7%, P < 0.05 vs. both). Furthermore, the expression of cyclooxygenase-2 (COX-2) and Bcl-2 was significantly elevated (+38% and +126%, respectively; P < 0.05) in myocardium of rabbits given nicorandil 24 h earlier versus controls. We conclude that nicorandil induces delayed cardioprotection against myocardial infarction similar to that afforded by the late phase of ischemic PC, possibly by upregulating COX-2 and Bcl-2.
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PMID:Nicorandil induces late preconditioning against myocardial infarction in conscious rabbits. 1468 73

Kallikrein/kinin has been shown to protect against ischemia/reperfusion-induced myocardial infarction and apoptosis. In the present study, we examined the potential neuroprotective action of kallikrein gene transfer in cerebral ischemia. Adult, male Sprague-Dawley rats were subjected to a 1-hour occlusion of the middle cerebral artery followed by intracerebroventricular injection of adenovirus harboring either the human tissue kallikrein gene or the luciferase gene. Kallikrein gene transfer significantly reduced ischemia-induced locomotor deficit scores and cerebral infarction after cerebral ischemia injury. Expression of recombinant human tissue kallikrein was identified and localized in monocytes/macrophages of rat ischemic brain by double immunostaining. Morphological analyses showed that kallikrein gene transfer enhanced the survival and migration of glial cells into the ischemic penumbra and core, as identified by immunostaining with glial fibrillary acidic protein. Cerebral ischemia markedly increased apoptotic cells, and kallikrein gene delivery reduced apoptosis to near-normal levels as seen in sham control rats. In primary cultured glial cells, kinin stimulated cell migration but inhibited hypoxia/reoxygenation-induced apoptosis in a dose-dependent manner. The effects of kinin on both migration and apoptosis were abolished by icatibant, a bradykinin B2 receptor antagonist. Enhanced cell survival after kallikrein gene transfer occurred in conjunction with markedly increased cerebral nitric oxide levels and phospho-Akt and Bcl-2 levels but reduced caspase-3 activation, NAD(P)H oxidase activity, and superoxide production. These results indicate that kallikrein gene transfer provides neuroprotection against cerebral ischemia injury by enhancing glial cell survival and migration and inhibiting apoptosis through suppression of oxidative stress and activation of the Akt-Bcl-2 signaling pathway.
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PMID:Kallikrein gene transfer protects against ischemic stroke by promoting glial cell migration and inhibiting apoptosis. 1469 96

Although increased Na(+)/H(+) exchanger type-1 (NHE-1) activity has been implicated in the pathogenesis of myocardial infarction, the role of NHE-1 in induction of apoptosis, and the potential mechanisms involved have not been fully characterized. This study tested the hypothesis that NHE-1 activity is involved in hypoxia (H)/re-oxygenation (Re)-induced cardiomyocyte apoptosis by increasing mitochondrial Ca(2+) ([Ca(2+)]m). Primary cultured neonatal rat cardiomyocytes were subjected to 4.5 h of H followed by 12 h of Re. Relative to H alone, the level of X-rhod-1 acetoxymethyl (AM)-labeled [Ca(2+)]m was increased, and the frequency of cell death (propidium iodide (PI) staining) and apoptotic cells (terminal deoxynucleotidyl transferase (TdT)-mediated-UTP nick end labeling [TUNEL]), confirmed by Annexin-V, were augmented at the end of Re, along with appearance of cytosolic cytochrome c, activation of caspase-3, and increased ratio of Bax and Bcl-2. Addition of cariporide (20 micromol/l), a well-known NHE-1 inhibitor, to cultured cells before H significantly reduced [Ca(2+)]m, the number of PI and TUNEL positive cells relative to the levels at end of Re, but did not completely eliminate these changes compared to Sham control. There was a strong trend for attenuation in increased levels of [Ca(2+)]m, and the number of PI and TUNEL positive cells when same dose of cariporide was added only at Re, but the difference in these variables did not reach significance. In contrast, the levels of [Ca(2+)]m and the number of PI and TUNEL positive cells were significantly reduced to a level comparable to Sham control when cariporide (20 micromol/l) was administered before H and during Re, respectively, associated with a reduction in cytosolic cytochrome c, caspase-3 activity and ratio of Bax and Bcl-2. In conclusion, these data suggest that NHE-1 is involved in induction of cardiomyocyte apoptosis during both H and Re through a [Ca(2+)]m-dependent manner, thereby resulting in activation of cytochrome c-caspase-3 signaling pathways.
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PMID:Involvement of Na+/H+ exchanger in hypoxia/re-oxygenation-induced neonatal rat cardiomyocyte apoptosis. 1497 1

Although human heme oxygenase-1 (hHO-1) could provide a useful approach for cellular protection in the ischemic heart, constitutive overexpression of hHO-1 may lead to unwanted side effects. To avoid this, we designed a hypoxia-regulated hHO-1 gene therapy system that can be switched on and off. This vigilant plasmid system is composed of myosin light chain-2v promoter and a gene switch that is based on an oxygen-dependent degradation domain from the hypoxia inducible factor-1-alpha. The vector can sense ischemia and switch on the hHO-1 gene system, specifically in the heart. In an in vivo experiment, the vigilant hHO-1 plasmid or saline was injected intramyocardially into myocardial infarction mice or sham operation mice. After gene transfer, expression of hHO-1 was only detected in the ischemic heart treated with vigilant hHO-1 plasmids. Masson trichrome staining showed significantly fewer fibrotic areas in vigilant hHO-1 plasmids-treated mice compared with saline control (43.0%+/-4.8% versus 62.5%+/-3.3%, P<0.01). The reduction of interstitial fibrosis is accompanied by an increase in myocardial hHO-1 expression in peri-infarct border areas, concomitant with higher Bcl-2 levels and lower Bax, Bak, and caspase 3 levels in the ischemic myocardium compared with saline control. By use of a cardiac catheter, heart from vigilant hHO-1 plasmids-treated mice showed improved recovery of contractile and diastolic performance after myocardial infarction compared with saline control. This study documents the beneficial regulation and therapeutic potential of vigilant plasmid-mediated hHO-1 gene transfer. This novel gene transfer strategy can provide cardiac-specific protection from future repeated bouts of ischemic injury.
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PMID:Protection from ischemic heart injury by a vigilant heme oxygenase-1 plasmid system. 1496 35

The aim of the present study was to determine the beneficial effect of mild hypothermia during ischemia and/or reperfusion injury in myocardial infarction. Sprague-Dawley rats (400 +/- 20 g) were subjected to 30 min occlusion of the left coronary artery followed by 24 h reperfusion. Rats were divided into normothermic (NT; 37 degrees C) and hypothermic (HT; 34 degrees C) groups. In the HT group hypothermia was maintained during coronary occlusion and continued for 30 min following reperfusion. Histological analysis revealed dead cardiomyocytes and polymorphonuclear neutrophil infiltration after 24 h. Myocardial infarction, measured using an image analyzer, showed that the percentage area of infarction was significantly decreased in the HT group. Immunohistochemical analysis was carried out using antibodies against Bcl-2, Bax and Bak. DNA fragments were labeled in situ using the 3'-OH end-labeling method (TUNEL). In the HT group Bcl-2 was induced in many myocytes, whereas Bax and Bak were induced in only a few myocytes. A higher number of TUNEL-positive cells were recorded in the NT group than in the HT group, but these were more thinly scattered in the HT group. The expression pattern revealed that many myocytes could survive at the border zone in the HT group; in contrast, few myocytes in the NT group were able to survive. Our results suggest that mild hypothermia selectively interferes with, and mitigates, reperfusion injury.
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PMID:Attenuation of ischemia and/or reperfusion injury during myocardial infarction using mild hypothermia in rats: an immunohistochemical study of Bcl-2, Bax, Bak and TUNEL. 1559 11

Adrenomedullin (AM) has been shown to protect against ischemia/reperfusion-induced myocardial infarction and apoptosis. In the present study, we examined the potential neuroprotective action of delayed AM gene transfer in cerebral ischemia. Three days after a 1-hr occlusion of the middle cerebral artery (MCAO), rats were injected intravenously with adenovirus harboring human AM cDNA. The experiment was terminated 7 days after MCAO. AM gene transfer significantly reduced cerebral infarct size compared with that of rats before virus injection and compared with that of rats injected with control virus. The expression of recombinant human AM was identified in ischemic brain by immunostaining. Morphological analyses showed that AM gene transfer enhanced the survival and migration of astrocytes into the ischemic core. Cerebral ischemia markedly increased astrocyte apoptosis, and AM gene delivery significantly reduced apoptosis to near normal levels as seen in sham control rats. Similarly, in primary cultured astrocytes, AM stimulated cell migration and inhibited hypoxia/reoxygenation-induced apoptosis. The effects of AM on both migration and apoptosis were abolished by calcitonin gene-related peptide [CGRP(8-37)], an AM receptor antagonist. Enhanced cell survival after AM gene transfer was accompanied by markedly increased cerebral nitric oxide and Bcl-2 levels, as well as Akt and GSK-3beta phosphorylation, but reduced NADPH oxidase activity and superoxide production. Inactivation of GSK-3beta by phosphorylation led to reduced GSK-3beta activity and caspase- 3 activation. These results indicate that exogenous AM provides neuroprotection against cerebral ischemia injury by enhancing astrocyte survival and migration and inhibiting apoptosis through suppression of oxidative stress-mediated signaling events.
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PMID:Adrenomedullin gene delivery protects against cerebral ischemic injury by promoting astrocyte migration and survival. 1568

To determine the temporal changes in oxidative stress, mitogen-activated protein (MAP) kinases and mitochondrial apoptotic proteins, and their relationship to myocyte apoptosis in the remote noninfarcted myocardium after myocardial infarction (MI), rabbits were randomly assigned to either coronary artery ligation to produce MI or sham operation. The animals were sacrificed at 1, 4, 8, or 12 weeks after coronary artery occlusion. Sham rabbits were sacrificed at 12 weeks after surgery. MI rabbits exhibited progressive increases of left ventricular (LV) end-diastolic pressure and end-diastolic dimension, and progressive decreases of LV fractional shortening and dP/dt over 12 weeks. The LV remodeling with LV chamber dilation and LV systolic dysfunction was temporally associated with progressive increases of cardiac oxidative stress as evidenced by decreased myocardial reduced-to-oxidized-glutathione ratio and increased myocardial 8-hydroxydeoxyguanosine and myocyte apoptosis. The ERK and JNK activities were decreased while p38 MAP kinase activity was increased with age of MI. The extent of p38 MAP kinase activation correlated with Bcl-2 phosphorylation. Bcl-2 protein was decreased in both mitochondrial and cytosolic fractions with age of MI. Bax protein was increased in both mitochondrial and cytosolic fractions. Cytochrome c was reduced in mitochondrial fraction and increased in cytosolic fraction in a time-dependent manner after MI. Cleaved caspase 9 and caspase 3 proteins were time-dependently increased after MI. These data suggest that p38 MAP kinase activation is not only time-dependent after MI, but also correlates with oxidative stress, Bcl-2 phosphorylation, and myocyte apoptosis. These changes in the remote noninfarcted myocardium may contribute to LV remodeling and dysfunction after MI.
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PMID:Progressive left ventricular remodeling, myocyte apoptosis, and protein signaling cascades after myocardial infarction in rabbits. 1594 20

Apoptosis is a common pathological feature in acute myocardial infarction (AMI). The infarct size is an important determinant of the prognosis of AMI. In recent years, Chinese medicinal herbs and their extracts have received great attention in prevention of AMI. The aim of this investigation was to evaluate the anti-ischemic effect of total flavones from Elsholtzia blanda (Benth.) Benth. (TFEB), a traditional Chinese medicine and to make clear the mechanism involved in it. Myocardial infarction was induced by coronary occlusion in rats. Apoptosis was measured quantitatively by the terminal transferase UTP nick end-labeling (TUNEL) method and confirmed by DNA laddering on agarose gel. The expression of anti-apoptotic protein, Bcl-2 and pro-apoptotic protein, Bax was visualized by Western blot analysis. TFEB significantly reduced infarct size and TUNEL-positive rate confirmed by disappearance of DNA laddering. Greater Bcl-2 and attenuated Bax expression was found in TFEB treating rats. These results suggest that TFEB reduce infarct size during AMI by inhibiting myocardial apoptosis through modulation of Bcl-2 family.
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PMID:Total flavones from Elsholtzia blanda reduce infarct size during acute myocardial ischemia by inhibiting myocardial apoptosis in rats. 1599 71

Cardiovascular disease is a leading cause of death worldwide. Loss of function or death of cardiomyocytes is a major contributing factor to these diseases. Cell death in conditions such as heart failure and myocardial infarction is associated with apoptosis. Apoptotic pathways have been well studied in non-myocytes and it is thought that similar pathways exist in cardiomyocytes. These pathways include death initiated by ligation of membrane-bound death receptors, release of pro-apoptotic factors from mitochondria or stress at the endoplasmic reticulum. The key regulators of apoptosis include inhibitors of caspases (IAPs), the Bcl-2 family of proteins, growth factors, stress proteins, calcium and oxidants. The highly organized and predictive nature of apoptotic signaling means it is amenable to manipulation. A thorough understanding of the apoptotic process would facilitate intervention at the most suitable points, alleviating myocardium decline and dysfunction. This review summarizes the mechanisms underlying apoptosis and the mediators/regulators involved in these signaling pathways. We also discuss how the potential therapeutic value of these molecules could be harnessed.
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PMID:Don't lose heart--therapeutic value of apoptosis prevention in the treatment of cardiovascular disease. 1620 9


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