Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The growing number of cellular and molecular pathways believed to be involved in mechanisms of ischemic cell death in the brain has spurred a similar growth in the number of potential neuroprotective modalities, the majority of which are pharmacological in nature. Preventing or minimizing the first few steps in the cascade of events leading to ischemic cell death would have a more profound effect on the postischemic outcome than intervention at later steps in that cascade. This logic is, of course, at the heart of the urgency in providing the stroke or cardiac arrest patient with the earliest possible neuroprotective treatment. For the purpose of assessing potential neuroprotective modalities, the use of a well-established cerebral hypoxic/ischemic model system is a prerequisite. In our studies, we have used two major approaches, in vitro and in vivo. We evaluated both agonists and antagonists of ionotropic glutamate receptor channels (IGRC) and their effects in exacerbating and attenuating, respectively, the posthypoxic/ischemic outcome. Other drugs were tested for their ability to block the L-type voltage-sensitive calcium channels (VSCC), which are responsible for calcium influx and overload upon hypoxia/ischemia. These two membrane protein entities, the IGRC and the VSCC, are believed to be involved in the early stages of the cellular cascade that leads to the demise of neurons posthypoxia/ischemia. Some of the drugs were also tested for possible interaction with each other searching for possible synergy. These and other published studies in the field are reviewed here.
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PMID:Neuroprotection against ischemic/hypoxic brain damage: blockers of ionotropic glutamate receptor and voltage sensitive calcium channels. 1547 50

Loss of ion homeostasis plays a central role in pathogenesis of ischemic cell damage. Ischemia-induced perturbation of ion homeostasis leads to intracellular accumulation of Ca2+ and Na+ and subsequent activation of proteases, phospholipases, and formation of oxygen and nitrogen free radicals. This signal transduction cascade results in long-term functional and structural changes in membrane and cytoskeletal integrity and eventual cell death. Both ion conductances and ion transporters could affect ion homeostasis. Considerable research effort has been centered on roles of passive fluxes via cation and anion conductances in cerebral ischemic damage. This review will instead focus on the recent studies into the role of secondary active transport proteins in ischemia-induced dissipation of ion homeostasis. Secondary active ion transport proteins are a membrane protein-mediated solute transport mechanism that derives its energy from the combined chemical gradients of the transported ions. They are important in maintaining steady-state intracellular ion concentrations. These include Na+-dependent chloride transport (NKCC), Na+/H+ exchange (NHE), and Na+/Ca2+ exchange (NCX). Results from both in vitro and in vivo experimental studies suggest that these ion transport proteins are potential targets to reduce or prevent ischemia-mediated loss of ion homeostasis.
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PMID:Role of membrane ion transport proteins in cerebral ischemic damage. 1712 36

Cellular prion protein (PrP(C)), a copper-binding glycosyl-phosphatidylinositol (GPI)-anchored membrane protein that is expressed predominantly in neurons can be induced in ischemia/hypoxic brain tissues. It was also found to be overexpressed and conferred multidrug resistance, promoting cancer metastasis and inhibiting apoptosis in gastric cancer in our lab. In solid tumors, hypoxia can promote malignant progression and confer resistance to chemotherapy by altering gene expression. In present study, we investigated the molecular mechanisms and signaling pathway involved in the induction of the PrP(C) gene by hypoxia in cancer cell lines. PrP(C) was detected to be upregulated in several cancer cell lines at both mRNA and protein level, and then found to be induced by hypoxia in a time-dependent manner. After hypoxia treatment, gastric cancer MKN28 cells transfected with luciferase reporter constructs of the human PrP(C) promoter, which contained HSE, expressed higher luciferase activities (4.3-fold) than those cells transfected with the constructs containing no HSE. In addition, the upregulation of PrP(C) was reduced by MERK/ERK inhibitor (PD98059). siRNA knockdown of PrP(C) could make the cells more sensitive to hypoxia induced drug sensitivity. In conclusion, from these findings, we can propose that some transcriptional factors phosphorylated by ERK1/2, could in turn interact with HSE in the promoter of PrP(C) resulting in upregulation of PrP(C) in gastric cancer cell line MKN28 during hypoxia. Downregulation of PrP(C) makes gastric cancer cells more sensitive to hypoxia induced drug sensitivity. However, other mechanisms might also be responsible for hypoxia induced overexpression of PrP(C) in gastric cancer.
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PMID:Hypoxia induced overexpression of PrP(C) in gastric cancer cell lines. 1738 71

The mammalian Na(+)/H(+) exchanger is a pH regulatory membrane protein that uses the sodium gradient to translocate one intracellular proton in exchange for one extracellular sodium. There are nine isoforms of the protein with varying tissue and cellular distribution, some isoforms are predominantly intracellular. In the myocardium, the Na(+)/H(+) exchanger type 1 isoform (NHE1) is the only plasma membrane isoform present in significant quantities. It plays an important role during ischemia/reperfusion damage to the myocardium and has recently been implicated in myocardial hypertrophy. The NHE1 gene is made from 12 exons and a differentially spliced version mediates Na(+)/Li(+) exchange. The NHE1 promoter is regulated by several transcription factors. In the myocardium, transcription factors both proximal and distal to the start site affect expression, including AP-2 and a thyroid responsive element. Recently, reactive oxygen species have also been shown to be important regulators of the NHE1 promoter. Structural and functional analysis of the NHE1 protein has shown that transmembrane segments IV, VII and IX are important in ion transport and susceptibility to pharmacological inhibition. NHE1 protein and mRNA levels are elevated by cardiac ischemia/reperfusion, hypertrophy and acidosis. Understanding the mechanism by which NHE1 mediates transport and its regulation of expression will give novel insights into its contributions in cardiovascular disease.
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PMID:Molecular biology of the myocardial Na+/H+ exchanger. 1819 41

Brain ischemia activates Ca(2+)-dependent synaptic vesicle exocytosis. The synaptosomal-associated protein 25 (SNAP-25) and syntaxin proteins, located on presynaptic terminals, are components of the SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) complex and play a key role in regulating exocytosis. Changes in the expression of SNAREs could affect SNARE complex formation, fusion of vesicles with the presynaptic membrane, and release of neurotransmitters through exocytosis. To investigate the relationship of glucose/oxygen deprivation (GOD)/reperfusion-induced neuronal damage and alteration of presynaptic function, we examined the expression of SNAREs and complexin during GOD and reperfusion using organotypic hippocampal slice cultures. Microtubule-associated protein 2 (MAP-2) staining and transmission electron microscopy showed that neuronal damage increased in a time-dependent manner and both types of neuronal death can occur at different times during GOD and reperfusion. The immunoreactivity of SNAREs such as SNAP-25, vesicle-associated membrane protein and syntaxin and complexin increased in pyramidal cell bodies in the CA1 and CA3 areas in a time-dependent manner following reperfusion. Our data suggest that alteration of presynaptic function may play a partial role in delayed neuronal death during GOD and reperfusion in organotypic hippocampal slice cultures.
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PMID:Glucose/oxygen deprivation and reperfusion upregulate SNAREs and complexin in organotypic hippocampal slice cultures. 1850 8

The Bcl-2 associated athanogene (BAG) family of proteins function as cochaperones by bridging molecules that recruit molecular chaperones to target proteins. BAG-1 provides a physical link between the heat shock proteins Hsc70/Hsp70 and the proteasome to facilitate ubiquitin-proteasome-mediated protein degradation. In addition to the proteasome, protein degradation via autophagy is responsible for maintaining cellular metabolism, organelle homeostasis and redox equilibrium. Our recent report shows that autophagy plays an important role in cardiac adaptation-induced cell survival against ischemia-reperfusion injury in association with the BAG-1 protein. BAG-1 is associated with the autophagosomal membrane protein LC3-II and it may participate in the induction of autophagy via Hsc70. Moreover, another BAG family member, BAG-3, is responsible for the induction of macroautophagy in association with HspB8. These results show the involvement of BAG family members in the induction of autophagy for the degradation of damaged or oxidized proteins to promote cell survival.
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PMID:BAG-1 induces autophagy for cardiac cell survival. 1900 66

The mammalian Na(+)/H(+) exchanger isoform 1 (NHE1) is a ubiquitously expressed membrane protein that regulates intracellular pH in the myocardium. NHE1 is also important in mediating myocardial hypertrophy, and the blockage of NHE1 activity prevents hypertrophy and reduces ischemia-reperfusion injury in animal models. We recently demonstrated that extracellular-regulated kinase (ERK)-mediated activation of NHE1 occurs during ischemia-reperfusion of the myocardium. To understand the regulation of NHE1 in the myocardium by phosphorylation, we expressed a series of adenoviruses that express wild-type and mutant cDNA for NHE1. All exogenous cDNA for NHE1 had additional mutations [Leu(163)Phe/Gly(174)Ser], which increases NHE1 resistance to EMD-87580 (a specific blocker of NHE1) 100-fold, and allowed the measurement of exogenous NHE1 while inhibiting endogenous NHE1. By examining the effects of a series of mutations of the NHE1 cytosolic region, we determined that the amino acids Ser(770) and Ser(771) were essential for the acute activation of NHE1 activity in rat cardiomyocytes. The specific mutation of either residue prevented the rapid activation of exchanger activity by a sustained intracellular acidosis through ERK-dependent pathways. The same amino acids were critical to phenylephrine-mediated, ERK-dependent activation of NHE1 activity and increased the phosphorylation in intact rat cardiomyocytes. The results demonstrate that both sustained intracellular acidosis and phenylephrine rapidly activate the NHE1 protein in intact cardiac cells through ERK-dependent pathways that act on a common pathway mediated by amino acids Ser(770) and Ser(771) of the cytosolic tail of the protein.
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PMID:Phenylephrine and sustained acidosis activate the neonatal rat cardiomyocyte Na+/H+ exchanger through phosphorylation of amino acids Ser770 and Ser771. 1954 84

The mammalian Na(+)/H(+) exchanger isoform 1 (NHE1) is a ubiquitously expressed membrane protein that regulates intracellular pH in the myocardium and other tissues. NHE1 is an important mediator of myocardial damage that occurs after ischemia-reperfusion injury. It has also been implicated in apoptotic damage in many tissues and its expression and activity are elevated in disease states in the myocardium. In this study, we examined the effect of additional exogenous NHE1 expression on isolated cardiomyocytes susceptibility to ischemia/reperfusion damage. Exogenous NHE1 elevated Na(+)/H(+) exchanger expression and activity when introduced into isolated cardiomyocytes through an adenoviral system. Isolated cardiomyocytes were subjected to simulated ischemia and reperfusion after infection with either control or NHE1-containing adenovirus. Cells were placed into an anaerobic chamber and effects of NHE1 expression after hypoxia/reoxygenation were examined. Hypoxia/reoxygenation increased caspase-3-like activity in controls, and the effect was greatly magnified in cells expressing NHE1 protein. It also elevated the percentage of apoptotic cardiomyocytes, which was also aggravated by expression of NHE1 protein. Hypoxia/reoxygenation also increased phospho-ERK levels. Elevated NHE1 expression was coincidental with increased expression of the ER stress protein, protein disulfide isomerase (PDI) and calreticulin (CRT). Our results demonstrate that increased NHE1 protein expression makes cells more susceptible to damage induced by hypoxia/reoxygenation in isolated cardiomyocytes. They suggest that elevated NHE1 in cardiovascular disease could predispose the human myocardium to enhanced apoptotic damage.
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PMID:Overexpression of the NHE1 isoform of the Na(+)/H (+) exchanger causes elevated apoptosis in isolated cardiomyocytes after hypoxia/reoxygenation challenge. 1994 39

The mammalian Na(+)/H(+) exchanger isoform 1 (NHE1) is a ubiquitously expressed pH-regulatory membrane protein that functions in the myocardium and other tissues. It is an important mediator of the myocardial damage that occurs after ischemia-reperfusion injury and is implicated in heart hypertrophy. Regulation of NHE1 has been proposed as a therapeutic target for cardioprotection. We therefore examined mechanisms of control of NHE1 in the myocardium. Several different amino acids have been implicated as a being critical to NHE1 regulation in a number of tissues including Ser(703), Ser(770), and Ser(771). In the myocardium, NHE1 is activated in response to a variety of stimuli including activation by an ERK-dependent sustained intracellular acidosis. In this study, we determined whether Ser(703) and p90(rsk) activity are critical in activation of NHE1 by sustained intracellular acidosis. In vitro phosphorylation of NHE1 C-terminal fusion proteins determined that ERK-dependent phosphorylation of the cytoplasmic region was not dependent on Ser(703); however, phosphorylation by p90(rsk) required Ser(703). A Ser703Ala mutation decreased basal NHE1 activity in CHO cells but not in cardiomyocytes. NHE1 with a Ser703Ala mutation was activated in response to sustained intracellular acidosis in CHO cells. In addition, sustained intracellular acidosis also activated the Ser703Ala mutant protein in isolated cardiomyocytes and phosphorylation levels were also increased by acidosis. The presence of a dominant-negative p90(rsk) kinase also did not prevent activation and phosphorylation of NHE1 by sustained intracellular acidosis in isolated cardiomyocytes. We conclude that Ser(703) and p90(rsk) are not required for activation by sustained intracellular acidosis and that p90(rsk) phosphorylation of Ser(703) is independent of this type of activation.
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PMID:Sustained intracellular acidosis activates the myocardial Na(+)/H(+) exchanger independent of amino acid Ser(703) and p90(rsk). 2047 61

Ankyrin polypeptides are critical for normal membrane protein expression in diverse cell types, including neurons, myocytes, epithelia, and erythrocytes. Ankyrin dysfunction results in defects in membrane expression of ankyrin-binding partners (including ion channels, transporters, and cell adhesion molecules), resulting in aberrant cellular function and disease. Here, we identify a new role for ankyrin-B in cardiac cell biology. We demonstrate that cardiac sarcolemmal K(ATP) channels directly associate with ankyrin-B in heart via the K(ATP) channel alpha-subunit Kir6.2. We demonstrate that primary myocytes lacking ankyrin-B display defects in Kir6.2 protein expression, membrane expression, and function. Moreover, we demonstrate a secondary role for ankyrin-B in regulating K(ATP) channel gating. Finally, we demonstrate that ankyrin-B forms a membrane complex with K(ATP) channels and the cardiac Na/K-ATPase, a second key membrane transporter involved in the cardiac ischemia response. Collectively, our new findings define a new role for cardiac ankyrin polypeptides in regulation of ion channel membrane expression in heart.
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PMID:Ankyrin-B regulates Kir6.2 membrane expression and function in heart. 2061 Mar 80


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