Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several cardioprotective proteins are induced during myocardial ischemia, such as heat shock proteins and anti-apoptotic Bcl-2-related proteins which, when experimentally overexpressed, have been shown to prevent ischemia-induced myocyte loss. As this pathophysiological induction is obviously not sufficient to prevent losses of myocytes, we analysed whether it could occur under moderate myocardial ischemia with hibernation, thus potentially contributing to myocyte protection under these conditions. Therefore, using anesthetized pigs with documented myocardial hypoperfusion and short-term hibernation, we investigated the left ventricular mRNA expression of the inducible heat shock protein Hsp70 and of the anti-apoptotic Bcl-XL in comparison with the pro-apoptotic Bak and Fas expression. For transcriptional analyses, the porcine cDNA sequences of Bcl-XL, Bak and Fas were identified by polymerase chain reaction (PCR) or by screening of a porcine heart cDNA library and cloned. Using reverse transcription polymerase chain reaction (RT-PCR), we observed an unchanged mRNA expression of inducible Hsp70, Bcl-XL, Bak and Fas after 85 min of hypoperfusion in the short-term hibernating myocardium, as well as after 30 min of subsequent reperfusion in the stunned myocardium, compared with transcription in a non-hypoperfused control area of the same ventricle. In conclusion, the mRNA expression of inducible Hsp70 and of several apoptosis-modulating proteins is not altered during moderate myocardial ischemia resulting in short-term hibernation of the affected area and during subsequent stunning.
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PMID:Quantification of cardioprotective gene expression in porcine short-term hibernating myocardium. 1007 23

The outcome of myocardial ischemia-reperfusion has been partially attributed to the degree of apoptosis in cardiomyocytes. Aggregating platelets by release of transforming growth factor-beta(1) (TGF-beta(1)) protect the isolated heart against ischemia-reperfusion injury and preserve myocardial TGF-beta(1) content. To gain more insight into the modulation of hypoxia-reoxygenation-induced injury (apoptosis and necrosis) to myocytes by TGF-beta(1) and aggregating platelets, cultured adult rat myocytes were exposed for 48 or 72 h to hypoxia alone, or to hypoxia followed by 3 h of reoxygenation. Apoptosis in the cells was determined by in situ terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling staining and DNA fragmentation on gel electrophoresis. Hypoxia alone caused a time-dependent increase in myocyte apoptosis (number of apoptotic cells: 19+/-3% at 48 h and 39+/-5% at 72 h compared with 5+/-1% in control cells, based on a 500-cell count). Three hours of reoxygenation after 48 h of hypoxia further increased the number of apoptotic cells (34+/-8 versus 19+/-3% in hypoxia for 48 h), but reoxygenation after 72 h of hypoxia did not additionally increase the number of apoptotic cells, perhaps because of extensive cell necrosis on prolonged hypoxia. Forty-eight hours of hypoxia followed by 3 h of reoxygenation also resulted in a decrease in Bcl-2 and an increase in Fas protein level. Incubation of myocytes with either recombinant TGF-beta(1) (0.5-5 ng/ml) or aggregated platelet supernatant (from 2-3 x10(7) platelets/ml, containing approximately 0.5 ng/ml of TGF-beta(1)) markedly (P<.01) decreased the number of apoptotic cells after hypoxia-reoxygenation. Incubation with TGF-beta(1) also reduced myocyte necrosis as evident from lactate dehydrogenase release and trypan blue dye exclusion. These data demonstrate that hypoxia-reoxygenation results in apoptosis and necrosis in cultured adult rat myocytes; this can be attenuated by TGF-beta(1). Similarity of data with TGF-beta(1) and aggregated platelet supernatant suggests that platelet-mediated cardioprotection during hypoxia-reoxygenation may relate in part to the release of TGF-beta(1).
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PMID:Hypoxia-reoxygenation-induced apoptosis in cultured adult rat myocytes and the protective effect of platelets and transforming growth factor-beta(1). 1052 94

Apoptosis has been implicated in ischemic heart disease, but its mechanism in cardiomyocytes has not been elucidated. In this study, we investigate the effects of hypoxia and reoxygenation in adult cardiomyocytes and the molecular mechanism involved in cardiomyocyte apoptosis. Morphologically, reoxygenation induced rounding up of the cells, appearance of membrane blebs that were filled with marginated mitochondria, and ultrastructural findings characteristic of apoptosis. Reoxygenation (18 hours of reoxygenation after 6 hours of hypoxia) and prolonged hypoxia (24 hours of hypoxia) resulted in a 59% and 51% decrease in cellular viability, respectively. During reoxygenation, cell death occurred predominantly via apoptosis associated with appearance of cytosolic cytochrome c and activation of caspase-3 and -9. However, nonapoptotic cell death predominated during prolonged hypoxia. Both caspase inhibition and Bcl-2 overexpression during reoxygenation significantly improved cellular viability through inhibition of apoptosis but had minimal effect on hypoxia-induced cell death. Bcl-2 overexpression blocked reoxygenation-induced cytochrome c release and activation of caspase -3 and -9, but caspase inhibition alone did not block cytochrome c release. These results suggest that apoptosis predominates in cardiomyocytes after reoxygenation through a mitochondrion-dependent apoptotic pathway, and Bcl-2 prevents reoxygenation-induced apoptosis by inhibiting cytochrome c release from the mitochondria and prevents activation of caspase-3 and -9.
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PMID:Morphological and molecular characterization of adult cardiomyocyte apoptosis during hypoxia and reoxygenation. 1090 95

The ability to sense and respond to changes in oxygen availability is critical for many developmental, physiological, and pathological processes, including angiogenesis, control of blood pressure, and cerebral and myocardial ischemia. Hypoxia-inducible factor-1alpha (HIF-1alpha) is a basic-helix-loop-helix (bHLH)containing member of the PER-ARNT-SIM (PAS) family of transcription factors that plays a central role in the response to hypoxia. HIF-1alpha, and its relatives HIF-2alpha/endothelial PAS domain protein (EPAS) and HIF-3alpha, are induced in response to hypoxia and serve to coordinately activate the expression of target genes whose products facilitate cell survival under conditions of oxygen deprivation. When cells are exposed to chronic hypoxia, the protective response can fail, resulting in apoptosis. This study shows that transcription of the gene encoding Nip3, a proapoptotic member of the Bcl-2 family of cell death factors, is strongly induced in response to hypoxia. The Nip3 promoter contains a functional HIF-1-responsive element (HRE) and is potently activated by both hypoxia and forced expression of HIF-1alpha. Exposure of cultured cells to chronic hypoxia results in the accumulation of a protein recognized by antibodies raised against Nip3. This study demonstrates a direct link between HIF-1alpha and a proapoptotic member of the Bcl-2 family and offers a reasonable physiological function for members of the Bcl-2 subfamily, including Nip3 and its close relative Nix. These observations indicate that Nip3 may play a dedicated role in the pathological progression of hypoxia-mediated apoptosis, as observed after ischemic injury.
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PMID:Expression of the gene encoding the proapoptotic Nip3 protein is induced by hypoxia. 1092 63

Two redox-sensitive transcription factors, AP-1 and NF-kappaB, have been implicated in the regulation of apoptosis induced by myocardial ischemia and reperfusion. Hearts adapted to ischemic stress by cyclic episodes of short durations of ischemia and reperfusion attenuate apoptotic cell death. This study was designed to examine the pattern of expression of these transcription factors and the redox sensitive transacting molecule, AP-1, NF-kappaB, and- Bcl-2, during ischemia/ reperfusion and myocardial adaptation to ischemia. NF-kappaB binding activity was low in nonischemic control heart. Fifteen minutes of ischemia resulted in translocation of NF-kappaB from cytosol to nucleus followed by activation. The binding activity of NF-kappaB was further enhanced after 60 min of ischemia. An even higher degree of NF-kappaB binding was noticed in the ischemically adapted myocardium. In contrast, AP-1 binding activity was highest for the hearts subjected to 15 min of ischemia followed by 2 hr of reperfusion. AP-1 binding was higher in the ischemically adapted heart as compared to the control. The Bcl-2 gene, which was found to be present in the control hearts, had lowered expression after 15 min of ischemia and 2 hr of reperfusion. Significant upregulation of Bcl-2 mRNA was noticed in the ischemically adapted hearts. Apoptotic cardiomyocytes were found only in the hearts that were reperfused for at least 90 min. No apoptosis occurred in hearts subjected up to 1 hr of ischemia or ischemic adaptation. Prolonged reperfusion, and not ischemia up to 1 hr, can induce cardiomyocyte apoptosis. In concert, ischemic/reperfusion increases the nuclear binding of both AP-1 and NF-kappaB, but downregulates Bcl-2 gene. Ischemic adaptation attenuates apoptotic cell death, further increases NF-kappaB binding activity and Bcl-2 gene induction, but reduces AP-1 binding activity. These results suggest that AP-1, NF-kappaB, and Bcl-2 are differentially regulated by ischemia/reperfusion and ischemic adaptation.
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PMID:Redox regulation of NF-kappaB and AP-1 in ischemic reperfused heart. 1122 43

Ischemic preconditioning (IPC) refers to the ability of short periods of ischemia to make the myocardium more resistant to a subsequent ischemic insult. It is the most powerful form of endogenous protection against myocardial infarction and has been demonstrated in all species evaluated to date. However, the cellular mechanisms that drive IPC remain poorly understood. This hypothesis describes an important role for alpha(1)-adrenoreceptors in mediating IPC and discusses the underlying mechanisms by which this is likely achieved. alpha(1)-Adrenoreceptors are present in the myocardium of all mammalian species, and several lines of evidence suggest that they play an important role in mediating IPC. During periods of myocardial hypoxia/ischemia, cardiomyocytes have to rely solely on anaerobic glycolysis for energy production; for this, the cells have to depend on increased glucose entry inside the cell as well as increased glycolysis. Stimulation of alpha(1)-adrenoreceptors increases glucose transport inside the cardiomyocytes by translocating glucose transporter (GLUT)-1 and GLUT-4 from the cytoplasm to the plasma membrane, enhances glycogenolysis by activating phosphorylase kinase, increases the rate of glycolysis by activating the enzyme phosphofructokinase, reduces intracellular acidity produced during excessive glycolysis by activating the Na(+)/H(+) exchanger, and inhibits apoptosis by increasing the levels of the antiapoptotic protein Bcl-2. Myocardial ischemia produces an increase in the expression of alpha(1)-adrenoreceptors in cardiomyocytes, as well as increases the levels of its agonist norepinephrine by several fold. During ischemic states, upregulation of alpha(1)-adrenoreceptors and increase in norepinephrine release could be a powerful adaptive mechanism that drives IPC. An understanding into the role of alpha(1)-adrenoreceptors in mediating IPC could not only point to newer treatments for limiting myocardial damage during myocardial infarction or heart surgery, but could also help in avoiding the use of alpha(1)-antagonists in patients with ischemic heart disease.
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PMID:Protecting the myocardium from ischemic injury: a critical role for alpha(1)-adrenoreceptors? 1129 92

Myocardial ischemia and reperfusion injury (MI/R) represents important sequelae of clinical events. Historically, a number of approaches including, surgical intervention, pharmacological therapy and physical exercise regimes have been prescribed for the treatment of patients with cardiovascular disease. Recently, however, attention has focused upon more novel approaches using gene-based therapies to treat cardiovascular and MI/R. This mini-review will examine the role that heat shock proteins (HSP), in particular the HSP70 family, and the antiapoptotic protein Bcl-2 play in myocardial protection. Also examined in this review are several techniques including adenovirus and Japan-Liposomal method for delivering genes into the myocardium.
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PMID:Gene therapy: a novel method for the treatment of myocardial ischemia and reperfusion injury--mini-review. 1139 69

Reperfusion after myocardial ischemia is associated with a rapid influx of calcium, leading to activation of various enzymes including calpain. Isolated perfused adult rabbit hearts subjected to global ischemia and reperfusion were studied. Calpain or a calpain-like activity was activated within 15 min after reperfusion, and preconditioning suppressed calpain activation. In contrast, caspase activation was not detected although cytochrome c was released after ischemia and reperfusion. The pro-apoptotic BH3-only Bcl-2 family member, Bid, was cleaved during ischemia/reperfusion in the adult rabbit heart. Recombinant Bid was cleaved by calpain to a fragment that was able to mediate cytochrome c release. The calpain cleavage site was mapped to a region within Bid that is extremely susceptible to proteolysis. These findings suggest that there is cross-talk between apoptotic and necrotic pathways in myocardial ischemia/reperfusion injury.
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PMID:Bid is cleaved by calpain to an active fragment in vitro and during myocardial ischemia/reperfusion. 1140 57

Coronary artery disease leads to injury and loss of myocardial tissue by deprivation of blood flow (ischemia) and is a major underlying cause of heart failure. Prolonged ischemia causes necrosis and apoptosis of cardiac myocytes and vascular cells; however, the mechanisms of ischemia-mediated cell death are poorly understood. Ischemia is associated with both hypoxia and acidosis due to increased glycolysis and lactic acid production. We recently reported that hypoxia does not induce cardiac myocyte apoptosis in the absence of acidosis. We now report that hypoxia-acidosis-associated cell death is mediated by BNIP3, a member of the Bcl-2 family of apoptosis-regulating proteins. Chronic hypoxia induced the expression and accumulation of BNIP3 mRNA and protein in cardiac myocytes, but acidosis was required to activate the death pathway. Acidosis stabilized BNIP3 protein and increased the association with mitochondria. Cell death by hypoxia-acidosis was blocked by pretreatment with antisense BNIP3 oligonucleotides. The pathway included extensive DNA fragmentation and opening of the mitochondrial permeability transition pore, but no apparent caspase activation. Overexpression of wild-type BNIP3, but not a translocation-defective mutant, activated cardiac myocyte death only when the myocytes were acidic. This pathway may figure significantly in muscle loss during myocardial ischemia.
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PMID:Hypoxia and acidosis activate cardiac myocyte death through the Bcl-2 family protein BNIP3. 1222 79

Previously we showed that cardiac fibroblasts are cellular targets of estrogen and that there are significant differences in proliferative response of male and female cardiac fibroblasts under hypoxia, a condition of myocardial ischemia. Here, we tested the hypothesis that signaling pathways that control cell cycle progression and apoptosis in cardiac fibroblasts may be activated in a gender-specific manner. Cardiac fibroblasts from adult, age-matched male and female rat heart were exposed to hypoxia (2% O2) and normoxia. Western analysis of cell lysate was used to compare the level of basal and hypoxia-induced expression of signal transduction proteins, known to control cell cycle progression and cell death. Hypoxia led to significant activation of MAP (mitogen-activated protein) kinase and Jun kinase pathways, as shown by phosphorylated extracellular signal-regulated kinase (ERK1/2) and Jun kinase isotypes in male cells but this effect was modest in female cells. Male cells expressed higher levels of basal expression for transcription factors c-jun and NF-kB as well as the inhibitor of NF-kB (lk-B). Although hypoxia did not induce changes in the level of c-Jun in either cell type, it moderately increased the level of NF-kB in male cells but led to its decrease in female cells. Basal and hypoxia-induced expression of cyclin D1, c-fos, and PCNA seemed to be comparable in both male and female cells. However, hypoxia-induced activation of cyclin B1, which occurred in both cells, was stronger in female cells. Basal expression of apoptosis-associated transcription factor, p53, was comparable in both cells. However, under hypoxia, there was an increase in the p53 level only in female cells. Although female cells showed higher basal expression for survival-associated protein, Bcl-2, the level of this protein remained unchanged under hypoxia in both cells. Together, these data demonstrate differences in basal and hypoxia-induced expression of proteins with an established role in cell cycle progression and apoptosis in male and female cardiac fibroblasts. These differences may further point to gender-related differences in signal transduction pathways that control the proliferative response of those cells under hypoxia.
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PMID:Gender-related differences in basal and hypoxia-induced activation of signal transduction pathways controlling cell cycle progression and apoptosis, in cardiac fibroblasts. 1237 61


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