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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To understand the complex mechanism(s) involved in molecular responses to ischemia, we developed two experimental models in pigs. In a "stunning" model of repetitive ischemia and reperfusion, we studied the mRNA expression of immediate early genes like c-fos, c-myc and heat shock protein-70 (HSP-70). Myocardial stunning was achieved by two cycles of 10-min left anterior descending coronary artery (LAD) occlusion and 30 min reperfusion. We observed several-fold enhanced expression of c-fos and HSP-70 mRNA in the stunned myocardium as compared with the control, whereas c-myc mRNA levels remained almost unchanged. In the second model, we examined the expression of the peptide mitogens heparin-binding growth factor 1 (HBGF-1) and transforming growth factor beta 1 (TGF-beta 1) after a chronic coronary artery occlusion leading to myocardial collateralization. Progredient stenosis of the circumflex coronary artery was induced by implanting a hygroscopic ameroid constrictor ring around it and occlusion was verified by in vivo angiography. Using polymerase chain reaction (PCR) and Northern hybridization techniques, we observed significantly enhanced expression of HBGF-1 and TGF-beta 1 in collateralized myocardium as compared with normal. In situ techniques revealed the localization of HBGF-1 transcripts in the blood vessel wall, and TGF-beta 1 in cardiac myocytes and Purkinje cells. Our results clearly indicate that myocardial stunning stimulates the expression of transcription factors which might be involved in regulation of certain growth factors like HBGF-1 and TGF-beta 1 which may play a significant role in the development of a collateral circulation.
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PMID:Molecular biology of the coronary vascular and myocardial responses to ischemia. 138 Jun 15

The molecular basis of myocardial adaptation to ischemia and reperfusion is poorly understood. It is thought that nuclear proto-oncogenes act as third messengers, converting cytoplasmic signal transduction into long-term changes of gene expression. We studied the expression of six nuclear proto-oncogenes (Egr-1, c-fos, fosB, c-jun, junB, and c-myc) in myocardium subjected to ischemia and reperfusion in anesthetized pigs. Stunning was achieved by two 10-minute left anterior descending coronary artery occlusions separated by 30 minutes of reperfusion. Hearts were excised after the first occlusion, after the first reperfusion, and at 30, 120, 150, and 210 minutes of reperfusion after the second occlusion. Total RNA was prepared from stunned as well as normally perfused myocardial tissue and subjected to Northern blotting. The response of the six nuclear proto-oncogenes varied.fosB gene expression was never detected. The c-myc gene was expressed, but its level was unchanged by ischemia. c-jun expression was slightly increased by ischemia (3.1 +/- 0.6-fold). The c-fos, Egr-1, and junB genes were highly induced, being fivefold to sevenfold higher in experimental than in control tissue. In three animals pretreated with the beta 1-antagonist metoprolol and then subjected to the above experimental protocol, the induction of proto-oncogenes was similar to that in nonblocked controls. Our results show that the myocardial adaptive response to ischemic stress includes the induction of at least four transcription factors that may be further operative in repair processes and angiogenesis.
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PMID:Proto-oncogene expression in porcine myocardium subjected to ischemia and reperfusion. 138 5

Steady-state levels of messenger RNA (mRNA) for different members of the heat-shock protein 70 gene family were studied in rat livers reperfused after non-necrogenic ischemia. The expression of constitutive hsc 73 gene decreases during ischemia, returns to normal upon reperfusion, and increases 4 hr after restoration of blood flow. Reperfusion induces the expression of another hsp 70 gene family member (the so-called inducible hsp 70 gene), which remains at high levels for at least 7 hr. The induction of hsp 70 family genes is preceded by activation of the cellular oncogene c-fos, the most prompt change in gene expression detected in reperfused liver. Run-on experiments demonstrate that the increased expression of these genes is largely dependent on activation of transcription. Changes in the amount of c-myc and ornithine decarboxylase mRNA are not evident, while the level of the mRNA for glucose-regulated protein GRP 78 increases later, concurrent with the onset of the acute phase response to surgical trauma. Analysis of polysomal and nonpolysomal fractions from sucrose gradients indicates that in postischemic liver, hsp 70 and hsc 73 mRNA are rapidly engaged on light polysomal or nonpolysomal complexes and are later shifted to polysomes. Albumin mRNA displays the same behavior, indicating that hsp 70 mRNA are not preferentially translated and that increased transcription is the major mechanism for enhanced hsp synthesis in postischemic liver. Damage by active oxygen species, pressure overload, and derangements of protein synthesis is likely to include the causative factors of increased expression of c-fos and the hsp 70 gene family in postischemic reperfused liver.
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PMID:Reprogramming of gene expression in postischemic rat liver: induction of proto-oncogenes and hsp 70 gene family. 210 73

To investigate how cardiac myocytes recover from a brief period of ischemia, we used a metabolic inhibition (MI) model, one of the in vitro ischemic models, of chick embryo ventricular myocytes, and examined the induction of immediate-early (IE) genes mRNAs and the activity of mitogen-activated protein (MAP) kinase. We performed Northern blot analysis to study the expression of c-jun, c-fos, and c-myc mRNAs during MI using 1 mM NaCN and 20 mM 2-deoxy-d-glucose, and also during the recovery from MI of 30 min. The c-fos mRNA was induced transiently at 30 and 60 min during the recovery. The expression of c-jun mRNA was significantly augmented at 30, 60, 90, and 120 min during the recovery (3.0-, 4.7-, 2.4-, and 1.9-fold induction, respectively) and so did the expression of c-myc mRNA (1.4-, 1.7-, 1.8-, and 2.0-fold induction, respectively). In contrast, the levels of these mRNAs remained unchanged during MI. The electrophoretic mobility shift assay revealed that AP-1 DNA binding activity markedly increased at 120 min during the recovery. When the cells were pretreated with protein kinase C (PKC) inhibitors, 100 microM H-7 or 1 microM staurosporine, the induction of c-jun mRNA at 60 min during the recovery was markedly suppressed (95 or 82% reduction, respectively). The c-jun induction was partially inhibited when the cells were treated with 2 mM EGTA during MI and the recovery (42% reduction). MAP kinase activity quantified with in-gel kinase assay was unchanged during MI, but significantly increased at 5, 10, and 15 min during the recovery (3.0-, 4.1-, and 3.4-fold increase, respectively). S6 kinase activity was also augmented significantly at 15 min during the recovery. Thus, these data suggest that IE genes as well as MAP kinase may play roles in the recovery process of cardiac myocytes from MI, and that the augmentation of c-jun expression needs the activation of PKC and to some extent, [Ca2+]i.
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PMID:Immediate-early gene induction and MAP kinase activation during recovery from metabolic inhibition in cultured cardiac myocytes. 761 38

Left ventricular hypertrophy (LVH) is an important independent risk factor for cardiovascular morbidity and mortality. Initially LVH improves contractility and pump function; however, over time a sequence of events occurs including disintegration of myofibrils, interstitial fibrosis, adenosine triphosphate depletion, and altered gene expression. Eventually the hypertrophied myocardium outgrows its capillary bed, subendocardial ischemia develops, and the heart fails. Hemodynamic (pressure) and nonhemodynamic signals (catecholamines, angiotensin II, thyroid hormone) have been identified that stimulate hypertrophic growth of the myocardium. Evidence is also accumulating that the induction of immediate early genes such as c-fos and c-myc may participate in the development of LVH.
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PMID:Cellular and signaling mechanisms of cardiac hypertrophy. 793 62

In aged individuals the incidence of heart failure is higher than in younger subjects. Ischemic events are also common in the aged heart because of changes in the coronary vasculature and myocytes caused by aging. Adaptational responses to increased hemodynamic overload and to ischemia in the aged heart are discussed at the molecular, cellular and organ levels. One characteristic of the aged heart is a limited capacity for adaptation with hypertrophy to increased mechanical load. This age-related attenuation of the hypertrophic response may be attributed to the diminished induction of proto-oncogenes such as c-fos, c-myc and c-jun by hemodynamic stress. This diminution results from the aging of the heart per se and may be modulated by extracardiac factors. An age-related diminution was also observed in the mRNA induction of heat shock proteins by transient ischemia. However, this diminished induction of immediate early genes in the aged heart was not observed after more severe stress. With regard to the coronary vasculature, the age at which pressure-overload begins seems to be one of the important factors which determine the vascularity of hypertrophied hearts. Late-onset pressure-overload decreased dilator reserve in spite of the absence of myocardial hypertrophy. Thus, the responses to stress in the aged heart are quite different from those in the young heart. The limited capacity for adaptation to hemodynamic overload and poor protective mechanisms against stress may be causes of the higher incidence of heart failure in the aged.
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PMID:Responses to hemodynamic stress in the aged heart. 796 46

Apoptosis, a form of cell death ("programmed" cell death) in which the nucleus and cytoplasm shrink and often fragment, serves to eliminate excessive or unwanted cells during remodeling of embryonic tissues, during organ involution, and in tumor regression. In acute pathological states, such as ischemia, the cells tend to swell and lyse--a process called necrosis. We hypothesize that the delayed neural death clinically associated with hypoxia may, in part, represent apoptosis. A tissue culture model of 24 hours of hypoxia was employed using sympathetic neurons. Pretreatment with an endonuclease inhibitor (aurintricarboxylic acid) decreased cell death by 53%, depolarizing conditions (55 mM potassium chloride) decreased cell death by 33%, and an RNA synthesis inhibitor (actinomycin D) by 26% (all have been shown to prevent apoptosis). Pretreatment with antisense c-myc had no effect. Fluorescent staining with propidium iodide (a DNA marker) demonstrated chromatin condensation and agarose gel electrophoresis demonstrated a DNA "ladder." These data suggest that apoptosis may play a role in hypoxic cell death and that in this paradigm, expression of c-myc is unnecessary. This would suggest a new approach to our understanding of hypoxia and open new strategies to lessen neuronal damage secondary to this process.
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PMID:Evidence for hypoxia-induced, programmed cell death of cultured neurons. 799 72

Regional and global myocardial ischemia and reperfusion have been demonstrated to induce expression of the stress response protein heat shock 70 (HSP70) and of immediate early genes, c-jun, c-fos, and c-myc. Because of the models that have been utilized, it has not been possible to discriminate whether this response is the consequence of ischemia, reperfusion, or abnormal hemodynamic stress superimposed on stunned myocardium. In a nonworking isolated and blood-perfused rat heart model, we evaluated the mRNAs for c-fos, c-myc, and hsp70. The heart was subjected to varying periods of ischemia and reperfusion. Significant increases in hsp70 and c-fos were observed, which increased with longer periods of ischemia. No significant increase in c-myc was measured. In addition, mRNA encoding the Ca2+/glucose responsive stress protein GRP78 was evaluated. No increase in this early response gene was noted despite the use of a model associated with cellular calcium loading. Based on these observations, we suggest that the induction of hsp70 and c-fos is the consequence of ischemia and reperfusion and not dependent upon an early hypertrophy response such as would be observed in afterload mismatching or on calcium loading. Further investigations are necessary to isolate the effects of ischemia from those of reperfusion.
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PMID:Myocardial stunning: association with altered gene expression. 806 49

Changes in gene expression including that of c-fos occur following cerebral ischemia. Proto-oncogenes c-myc and s-myc and oncosuppressor gene p53 are known to induce apoptosis in some types of cells, whereas proto-oncogene bcl-2 inhibits apoptosis. Possible induction of mRNAs for c-myc, N-myc, s-myc, c-fos, p53 and bcl-2 was examined following focal ischemia in the rat anterior cortex, hippocampus, thalamus and cerebellum by Northern blot analysis. Animals were decapitated 1, 2, 6, 12, and 24 hours following the left middle cerebral artery (MCA) occlusion. In sham-operated control rats, the mRNAs for c-myc, N-myc, c-fos and p53 were present in the anterior cortex, hippocampus, thalamus on both sides, and in the cerebellum, whereas those for s-myc and bcl-2 were not. The c-myc gene expression was rapidly and markedly induced by the MCA occlusion in the ipsilateral anterior cortex, hippocampus and thalamus in a time-dependent manner. In these regions, the c-fos gene expression was also induced as early as 1 hour after the MCA occlusion. The p-53 mRNA was induced in the ipsilateral hippocampus at 24 hours after MCA occlusion. In contrast, mRNAs for N-myc, s-myc and bcl-2 were not induced following MCA occlusion. These results indicate a possibility that high-level expression of the c-myc gene may be involved in the ischemic cellular events including apoptosis.
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PMID:Up-regulation of c-myc gene expression following focal ischemia in the rat brain. 898 58

Apoptosis is well described in invertebrates and recently documented in mammals. The prevalence and pathophysiology of mammalian apoptosis is unknown and may have clinical ramifications. The aim of this study is to investigate the apoptotic response during kidney ischemia-reperfusion (I/R) injury. Kidney I/R was initiated in anesthetized rats by occlusion of the renal pedicle for 45 min with or without pretreatment with .2 mg/kg verapamil: control animals received sham exposure. Flow was re-established after ischemia and the animals were allowed to recover for 24 h. Bilateral kidneys were harvested for DNA electrophoresis, Western analysis for p53, Northern analysis for c-myc expression, and light and electron microscopic analysis. Kidney I/R caused characteristic DNA laddering in the clamped kidney, and less extensive laddering was seen in the contralateral kidney. Light and electron microscopic analysis confirmed apoptotic morphology in the reperfused tissues. Verapamil pretreatment completely abolished DNA laddering and attenuated the microscopic evidence of apoptosis. p53 levels were increased by I/R in the ischemic kidney and moderately increased in the contralateral organ. c-myc mRNA levels were increased by the I/R insult. Kidney I/R injury may induce global apoptosis, which seems to be associated with an alteration in calcium homeostasis. The increase in p53 and c-myc mRNA levels seen with I/R may facilitate apoptosis. Calcium modulation seems to reduce apoptosis during I/R and may have therapeutic implications.
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PMID:Calcium blockade reduces renal apoptosis during ischemia reperfusion. 937 65


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