Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In unstable angina, there are data to suggest a substantial risk of recurrent ischemia, infarction, and death when early angiography and/or revascularization have been deferred. Conversely, it has been suggested that early angiography and revascularization are more dangerous than deferred procedures. Critical review of the literature, however, suggests that there is no specific risk inherent in early intervention, but rather that patients who cannot wait are at higher risk anyway. The most valuable data on the comparison of an "early invasive" and a "conservative" strategy in unstable angina come from the Thrombolysis in Myocardial Ischemia (TIMI) IIIB study. The results show no major difference in outcome between groups (despite a high intervention rate in the conservative group), but a shorter hospital stay, lower drug use, and fewer rehospitalizations in the group treated according to the early invasive strategy. These results have been interpreted as favoring early intervention, due to the potential for a shorter hospital stay (a major determinant of cost in many countries) because of the possibility of achieving complete diagnosis and treatment within several days of admission, with good results. In addition, since the inception of the TIMI IIIB study, there have been major improvements in the field of angioplasty, such as the increased use of stents and the availability of safe and effective glycoprotein (GP) IIb-IIIa inhibitors. Thus, the pathophysiology, the excellent results of early intervention, and the recent improvements in angioplasty and its medical and pharmacologic environment, provide a strong rationale for early intervention.
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PMID:Revascularization of patients with unstable coronary artery disease: the case for early intervention. 929 70

The aim of this study was to look at the role of alpha 1-acid glycoprotein as a natural anti-inflammatory agent with particular respect to its antineutrophil and anticomplement activity. A recombinantly engineered form of sialyl Lewisx (sLe(x))-bearing alpha 1-acid glycoprotein (sAGP) was administered intravenously to pentobarbital-anesthetized rats after 50 min of intestinal ischemia just before 4 h of reperfusion. A non-sLe(x)-bearing form of AGP (nsAGP) was used as control. sAGP-treated animals had a 62% reduction (P < 0.05) in remote lung injury, assessed by 125I-albumin permeability, compared with those treated with nsAGP (permeability index of 3.61 +/- 0.15 x 10(-3) and 5.18 +/- 0.67 x 10(-3), respectively). There was a reduction in pulmonary myeloperoxidase levels in sAGP-treated rats compared with nsAGP-treated rats. Complement-dependent intestinal injury, assessed by 125I-albumin permeability was reduced by 28% (P < 0.05) in animals treated with sAGP (7.58 +/- 0.63) compared with those treated with nsAGP (10.4 +/- 0.54). We conclude that sAGP ameliorates both complement- and neutrophil-mediated injuries.
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PMID:alpha 1-Acid glycoprotein reduces local and remote injuries after intestinal ischemia in the rat. 937 99

The middle domain of plasma histidine-proline-rich glycoprotein (HPRG) contains unusual tandem pentapeptide repeats (consensus G(H/P)(H/P)PH) and binds heparin and transition metals. Unlike other proteins that interact with heparin via lysine or arginine residues, HPRG relies exclusively on histidine residues for this interaction. To assess the consequences of this unusual requirement, we have studied the interaction between human plasma HPRG and immobilized glycosaminoglycans (GAGs) using resonant mirror biosensor techniques. HPRG binding to immobilized heparin was strikingly pH-sensitive, producing a titration curve with a midpoint at pH 6.8. There was little binding of HPRG to heparin at physiological pH in the absence of metals, but the interaction was promoted by nanomolar concentrations of free zinc and copper, and its pH dependence was shifted toward alkaline pH by zinc. The affinity of HPRG for various GAGs measured in a competition assay decreased in the following order: heparin > dermatan sulfate > heparan sulfate > chondroitin sulfate A. Binding of HPRG to immobilized dermatan sulfate had a midpoint at pH 6.5, was less influenced by zinc, and exhibited cooperativity. Importantly, plasminogen interacted specifically with GAG-bound HPRG. We propose that HPRG is a physiological pH sensor, interacting with negatively charged GAGs on cell surfaces only when it acquires a net positive charge by protonation and/or metal binding. This provides a mechanism to regulate the function of HPRG (the local pH) and rationalizes the role of its unique, conserved histidine-proline-rich domain. Thus, under conditions of local acidosis (e.g. ischemia or hypoxia), HPRG can co-immobilize plasminogen at the cell surface as well as compete for heparin with other proteins such as antithrombin.
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PMID:Histidine-proline-rich glycoprotein as a plasma pH sensor. Modulation of its interaction with glycosaminoglycans by ph and metals. 948 72

Axon injury rapidly activates microglial and astroglial cells close to the axotomized neurons. Following motor axon injury, astrocytes upregulate within hour(s) the gap junction protein connexin-43, and within one day glial fibrillary acidic protein (GFAP). Concomitantly, microglial cells proliferate and migrate towards the axotomized neuron perikarya. Analogous responses occur in central termination territories of peripherally injured sensory ganglion cells. The activated microglia express a number of inflammatory and immune mediators. When neuron degeneration occurs, microglia act as phagocytes. This is uncommon after peripheral nerve injury in the adult mammal, however, and the functional implications of the glial cell responses in this situation are unclear. When central axons are injured, the glial cell responses around the affected neuron perikarya appears to be minimal or absent, unless neuron degeneration occurs. Microglia proliferate, and astrocytes upregulate GFAP along central axons undergoing anterograde, Wallerian, degeneration. Although microglia develop into phagocytes, they eliminate the disintegrating myelin very slowly, presumably because they fail to release molecules which facilitate phagocytosis. During later stages of Wallerian degeneration, oligodendrocytes express clusterin, a glycoprotein implicated in several conditions of cell degeneration. A hypothetical scheme for glial cell activation following axon injury is discussed, implying the injured neurons initially interact with adjacent astrocytes. Subsequently, neighbouring resting microglia are activated. These glial reactions are amplified by paracrine and autocrine mechanisms, in which cytokines appear to be important mediators. The specific functional properties of the activated glial cells will determine their influence on neuronal survival, axon regeneration, and synaptic plasticity. The control of the induction and progression of these responses are therefore likely to be critical for the outcome of, for example, neurotrauma, brain ischemia and chronic neurodegenerative diseases.
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PMID:Central neuron-glial and glial-glial interactions following axon injury. 960 98

A major mechanism by which the heart adapts to intracellular acidosis during ischemia and recovers from the acidosis after reperfusion is through the sodium-hydrogen exchanger (NHE). There are at least 5 NHE isoforms thus-far identified with the NHE-1 subtype representing the major one found in the mammalian myocardium. This 110 kDa glycoprotein extrudes protons concomitantly with Na influx in a 1:1 stoichiometric relationship rendering the process electroneutral. Although NHE is critical for the maintenance of intracellular pH during acid loading conditions such as ischemia, there is convincing evidence that it also plays a pivotal role in mediating tissue injury during ischemia and reperfusion. The mechanism for this paradoxical deleterious role of NHE reflects the fact that under conditions of tissue stress, including ischemia, Na-K adenosine triphosphate (ATP)ase is inhibited thereby limiting Na extrusion resulting in an elevation in intracellular Na concentrations. The latter effect, in turn, will increase intracellular Ca concentrations via Na-Ca exchange. In addition, NHE-1 expression in the diseased myocardium is increased suggesting that elevated production of the antiporter represents a long-term adaptive process in an attempt by the cardiac cell to regulate intracellular pH which, paradoxically, contributes to cardiac pathology. Extensive studies using NHE inhibitors such as amiloride or its analogs, or more specific compounds including 3-methylsulphonyl-4-piperidinoloenzoyl-guanidine methanesulphonate (HOE 694) or 4-isopropyl-3-methylsulphonylbenzcyl-guanidine methane sulphonate (HOE 642) have consistently shown protective effects against ischemic and reperfusion injury in a large variety of experimental models and animal species particularly in terms of attenuating contractile dysfunction. Such studies have contributed greatly to the overwhelming evidence that NHE activation mediates ischemic and reperfusion injury. Indeed, HOE 642 (Cariporide) is currently undergoing clinical evaluation in high risk cardiac patients. Moreover, there is now emerging evidence that NHE may be involved in mediating cardiotoxicity directly produced by various ischemic metabolites such as lipid amphiphiles or reactive oxygen species. In this regard, we have demonstrated that NHE inhibitors can effectively attenuate the cardiac injury produced by lysophosphatidylcholine and hydrogen peroxide. In addition, it now appears that NHE inhibition reduces apoptosis in the ischemic myocardium, a process which may be of importance in the subsequent development of postinfarction heart failure. In conclusion, NHE represents an important adaptive process in response to intracellular acidosis resulting in a paradoxical contribution to cardiac tissue injury.
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PMID:The myocardial sodium-hydrogen exchanger (NHE) and its role in mediating ischemic and reperfusion injury. 965 15

Acute renal failure (ARF) as a consequence of ischemic injury is a common disease affecting 5% of the hospitalized population. Despite the fact that mortality from ARF is high, there has been little improvement in survival rates over the last 40 years. The pathogenesis of ARF may be related to substantial changes in cell-cell and cell-extracellular matrix interactions mediated by beta1-integrins. On the basis of in vitro and in vivo studies, reorganization of beta1-integrins from basal to apical surfaces of injured tubular epithelia has been suggested to facilitate epithelial detachment, contributing to tubular obstruction and backleak of glomerular filtrate. In this study, we examine integrin and extracellular matrix dynamics during epithelial injury and repair using an in vivo rat model of unilateral ischemia. We find that, soon after reperfusion, beta1-integrins newly appear on lateral borders in epithelial cells of the S3 segment but are not on the apical surface. At later times, as further injury and regeneration coordinately occur, epithelia adherent to the basement membrane localize beta1 predominantly to basal surfaces even while the polarity of other marker proteins is lost. At the same time, amorphous material consisting of depolarized exfoliated cells fills the luminal space. Notably, beta1-integrins are not detected on exfoliated cells. A novel finding is the presence of fibronectin, a glycoprotein of plasma and the renal interstitium, in tubular spaces of the distal nephron and to a lesser extent S3 segments. These results indicate that beta1-integrins dramatically change their distribution during ischemic injury and epithelial repair, possibly contributing to cell exfoliation initially and to epithelial regeneration at later stages. Together with the appearance of large amounts of fibronectin in tubular lumens, these alterations may play a significant role in the pathophysiology of ARF.
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PMID:Polarity, integrin, and extracellular matrix dynamics in the postischemic rat kidney. 973 Sep 55

Ischemia and reperfusion (I/R) induces neutrophil infiltration in skeletal muscle that is localized to the ischemic region. To transmigrate at ischemic regions, granulocytes must first arrest in the postcapillary venular segment of the microcirculation. Initially, leukocytes roll along the endothelium of these venules, a weak adhesive interaction that is mediated by the selectins (L-, E-, and P-selectin). Leukocyte rolling functions to slow the neutrophil during its transit through the microcirculation, thereby allowing it to monitor its local environment for the presence of activating factors arising from the ischemic tissues. When activated, the rolling granulocyte is rendered capable of forming the stronger adhesive interactions that allow the cell to become arrested in postcapillary venules in the ischemic region. These adhesive interactions are mediated by a leukocyte glycoprotein complex designated CD11/CD18 and intercellular adhesion molecule-1 (ICAM-1) expressed on endothelial cells. The stationary neutrophil uses the gradient in concentration of soluble chemoattractants liberated from ischemic tissues as a directional cue to move from the vascular to extravascular compartment, being guided in its transit across the endothelium by interactions with platelet endothelial cell adhesion molecule-1 (PECAM-1), an adhesive molecule localized to the interendothelial cleft. This paper reviews current understanding of the mechanisms underlying the establishment of leukocyte/endothelial cell interactions in postischemic skeletal muscle in terms of specific adhesion molecules that participate in neutrophil sequestration after I/R. Discovery of the molecular determinants of neutrophil/endothelial cell adhesion has uncovered potential mechanisms whereby agents exhibiting anti-adhesive properties may act. The micronized purified flavonoid fraction (450 mg diosmin, 50 mg hesperidin) prevents I/R-induced leukocyte adhesion in skeletal muscle. This anti-adhesive effect appears to be mediated at least in part by inhibition of induced expression of ICAM-1.
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PMID:Adhesion molecule expression in postischemic microvascular dysfunction: activity of a micronized purified flavonoid fraction. 1047 47

Prevention of myocardial necrosis in acute coronary syndromes is the immediate goal of therapy. Decreasing myocardial oxygen needs is of marginal value. Improving oxygen delivery by mechanical or thrombolytic reperfusion is more successful but still leaves much to be desired in terms of time to reperfusion before damage occurs due to reperfusion itself. During ischemia, there is a metabolic mismatch between glycolysis and glucose oxidation that results in accumulation of hydrogen ions, which, in turn, activates the Na+/H+ exchange system (NHE-1), leading to Na+ and Ca2+ overload and cell death. Blocking NHE-1 is a new strategy designed to prevent or delay cell death. Cariporide, a potent inhibitor of the NHE-1 system, is currently under investigation. Other agents under investigation are designed to modify proton generation, modify proton effects, and attenuate necrosis progression. Also under study are agents designed to mediate preconditioning (adenosine agonists and adenosine triphosphate-sensitive potassium channel openers). Other approaches to minimize cell injury include use of antioxidants and free-radical scavengers, complement inhibitors, selectin blockers, and glycoprotein (GP) IIb/IIIa antagonists.
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PMID:Protection of the myocardial cell during ischemia. 1048 74

The Na(+)-H(+) exchange (NHE) is a major mechanism by which the heart adapts to intracellular acidosis during ischemia and recovers from the acidosis after reperfusion. There are at least 6 NHE isoforms thus far identified with the NHE1 subtype representing the major one found in the mammalian myocardium. This 110-kDa glycoprotein extrudes protons concomitantly with Na(+) influx in a 1:1 stoichiometric relationship rendering the process electroneutral, and its activity is regulated by numerous factors, including phosphorylation-dependent processes. There is convincing evidence that NHE mediates tissue injury during ischemia and reperfusion, which probably reflects the fact that under conditions of tissue stress, including ischemia, Na(+)-K(+) ATPase is inhibited, thereby limiting Na(+) extrusion, resulting in an elevation in [Na(+)](i). The latter effect, in turn, will increase [Ca(2+)](i) via Na(+)-Ca(2+) exchange. In addition, NHE1 mRNA expression is elevated in response to injury, which may further contribute to the deleterious consequence of pathological insult. Extensive studies using NHE inhibitors have consistently shown protective effects against ischemic and reperfusion injury in a large variety of experimental models and has led to clinical evaluation of NHE inhibition in patients with coronary artery disease. Emerging evidence also implicates NHE1 in other cardiac disease states, and the exchanger may be particularly critical to postinfarction remodeling responses resulting in development of hypertrophy and heart failure.
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PMID:The myocardial Na(+)-H(+) exchange: structure, regulation, and its role in heart disease. 1053 45

Stanniocalcin (STC) is a glycoprotein hormone originally found in bony fish, in which it regulates calcium/phosphate homeostasis and protects against hypercalcemia. The recently characterized human STC shows about 70% homology with fish STC. We previously reported a constitutive expression of STC in terminally differentiated neurons. Here, we show that exposure of human neural-crest-derived cell line Paju to hypercalcemic culture medium induced expression of STC. Treatment of Paju cells with recombinant human STC increased their uptake of inorganic phosphate. Paju cells expressing STC by cDNA transfection displayed increased resistance to ischemic challenge and to elevated intracellular free calcium induced by treatment with thapsigargin. An up-regulated and redistributed expression of STC was observed in neurons surrounding the core of acute infarcts in human and rat brains. Given that mobilization and influx of calcium is considered a main neurotoxic mechanism following ischemia, our results suggest that the altered expression of STC contributes to the protection of cerebral neurons against hypoxic/ischemic damage. Manipulation of the STC expression may therefore offer a therapeutic approach to limit the injury after ischemic brain insults.
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PMID:Stanniocalcin: A molecular guard of neurons during cerebral ischemia. 1072 97


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