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 sodium-calcium exchanger (NCX) is a critical mediator of calcium homeostasis. In the heart, NCX1 predominantly operates in forward mode to extrude Ca(2+); however, reverse-mode NCX1 activity during ischemia/reperfusion (IR) contributes to Ca(2+) loading and electrical and contractile dysfunction. IR injury has also been associated with altered fat metabolism and accumulation of long-chain acyl CoA esters. Here, we show that acyl CoAs are novel, endogenous activators of reverse-mode NCX1 activity, exhibiting chain length and saturation dependence, with longer chain saturated acyl moieties being the most effective NCX1 activators. These results implicate dietary fat composition as a plausible determinant of IR injury. We further show that acyl CoAs may interact directly with the XIP (exchanger inhibitory peptide) sequence, a known region of anionic lipid modulation, to dynamically regulate NCX1 activity and Ca(2+) homeostasis. Additionally, our findings have broad implications for the coupling of Ca(2+) homeostasis to fat metabolism in a variety of tissues.
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PMID:Metabolic regulation of sodium-calcium exchange by intracellular acyl CoAs. 1697 18

Nitric oxide (NO) plays a protective role in myocardial ischemia-reperfusion (I/R) injury. However, the concomitant production of superoxide and other reactive oxygen species (ROS) during I/R may diminish the bioavailability of NO and hence compromise the beneficial effects. The objective of this study was to investigate the protective effect of the coadministration of NCX-4016 [2-(acetyloxy)benzoic acid 3-(nitrooxymethyl)phenyl ester] (an NO donor) with antioxidants Tempol, superoxide dismutase (SOD), or urate on I/R injury. Isolated rat hearts, perfused with Krebs-Henseleit buffer, were subjected to 30 minutes of global ischemia, followed by 45 minutes of reperfusion. Before the induction of ischemia, the hearts were infused for 1 minute with NCX-4016 (100 microM) either alone or in combination with Tempol (100 microM), SOD (200 U/mL), or urate (100 microM). Hearts pretreated with NCX-4016 showed a significantly enhanced recovery of function and decreased infarct size and LDH/CK release compared with the controls. However, treatment of hearts with NCX-4016 + Tempol, SOD, or urate showed a significantly enhanced recovery of heart function compared with NCX-4016 alone. The treatment of hearts with NCX-4016 + Tempol showed significantly enhanced NO generation and decreased ROS and dityrosine (a marker of peroxynitrite) formation. In conclusion, NCX-4016 in combination with Tempol demonstrated significant cardioprotection and, thus, may offer a novel therapeutic strategy to prevent I/R-mediated myocardial injury.
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PMID:Prevention of postischemic myocardial reperfusion injury by the combined treatment of NCX-4016 and Tempol. 1703 Dec 60

Na(+)-K(+)-Cl(-) cotransporter isoform 1 (NKCC1) and reverse mode operation of the Na(+)/Ca(2+) exchanger (NCX) contribute to intracellular Na(+) and Ca(2+) overload in astrocytes following oxygen-glucose deprivation (OGD) and reoxygenation (REOX). Here, we further investigated whether NKCC1 and NCX play a role in mitochondrial Ca(2+) (Ca(m)(2+)) overload and dysfunction. OGD/REOX caused a doubling of mitochondrial-releasable Ca(2+) (P < 0.05). When NKCC1 was inhibited with bumetanide, the mitochondrial-releasable Ca(2+) was reduced by approximately 42% (P < 0.05). Genetic ablation of NKCC1 also reduced Ca(m)(2+) accumulation. Moreover, OGD/REOX in NKCC1(+/+) astrocytes caused dissipation of the mitochondrial membrane potential (Psi(m)) to 42 +/- 3% of controls. In contrast, when NKCC1 was inhibited with bumetanide, depolarization of Psi(m) was attenuated significantly (66 +/- 10% of controls, P < 0.05). Cells were also subjected to severe in vitro hypoxia by superfusion with a hypoxic, acidic, ion-shifted Ringer buffer (HAIR). HAIR/REOX triggered a secondary, sustained rise in intracellular Ca(2+) that was attenuated by reversal NCX inhibitor KB-R7943. The hypoxia-mediated increase in Ca(m)(2+) was accompanied by loss of Psi(m) and cytochrome c release in NKCC1(+/+) astrocytes. Bumetanide or genetic ablation of NKCC1 attenuated mitochondrial dysfunction and astrocyte death following ischemia. Our study suggests that NKCC1 acting in concert with NCX causes a perturbation of Ca(m)(2+) homeostasis and mitochondrial dysfunction and cell death following in vitro ischemia.
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PMID:Role of Na+-K+-Cl- cotransport and Na+/Ca2+ exchange in mitochondrial dysfunction in astrocytes following in vitro ischemia. 1703 99

This study examined Ca(2+) handling mechanisms involved in cardioprotection induced by chronic intermittent hypoxia (CIH) against ischemia-reperfusion (I/R) injury. Adult male Sprague-Dawley rats were exposed to 10% inspired O(2) continuously for 6 h daily from 3, 7, and 14 days. In isolated perfused hearts subjected to I/R, CIH-induced cardioprotection was most significant in the 7-day group with less infarct size and lactate dehydrogenase release, compared with the normoxic group. The I/R-induced alterations in diastolic Ca(2+) level, amplitude, time-to-peak, and the decay time of both electrically and caffeine-induced Ca(2+) transients measured by spectrofluorometry in isolated ventricular myocytes of the 7-day CIH group were less than that of the normoxic group, suggesting an involvement of altered Ca(2+) handling of the sarcoplasmic reticulum (SR) and sarcolemma. We further determined the protein expression and activity of (45)Ca(2+) flux of SR-Ca(2+)-ATPase, ryanodine receptor (RyR) and sarcolemmal Na(+)/Ca(2+) exchange (NCX) in ventricular myocytes from the CIH and normoxic groups before and during I/R. There were no changes in expression levels of the Ca(2+)-handling proteins but significant increases in the RyR and NCX activities were remarkable during I/R in the CIH but not the normoxic group. The augmented RyR and NCX activities were abolished, respectively, by PKA inhibitor (0.5 microM KT5720 or 0.5 microM PKI(14-22)) and PKC inhibitor (5 microM chelerythrine chloride or 0.2 microM calphostin C) but not by Ca(2+)/calmodulin-dependent protein kinase II inhibitor KN-93 (1 microM). Thus, CIH confers cardioprotection against I/R injury in rat cardiomyocytes by altered Ca(2+) handling with augmented RyR and NCX activities via protein kinase activation.
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PMID:Chronic intermittent hypoxia alters Ca2+ handling in rat cardiomyocytes by augmented Na+/Ca2+ exchange and ryanodine receptor activities in ischemia-reperfusion. 1726 48

Ischemia/reperfusion damage evokes systemic inflammation and endothelial dysfunction in patients with intermittent claudication. We compared the effects of aspirin with those of a nitric oxide-donating aspirin in preventing the acute, systemic endothelial dysfunction provoked by exercise-induced ischemia of the lower limbs in patients with intermittent claudication. In a prospective, randomized, single-blind, parallel-groups trial among 44 patients with intermittent claudication we compared four weeks of aspirin (100 mg o.d.) with NCX 4016 (800 mg b.i.d.). Primary end point was the exercise-induced changes in brachial flow-mediated vasodilation (FMD) at day 28; secondary end points were effort-induced changes of markers of neutrophil (plasma elastase) and endothelial (soluble VCAM-1) activation. Baseline FMD was comparable in the two groups, both on day 1 (pre-treatment: aspirin = 3.1 +/- 0.5%, nitroaspirin = 3.9 +/- 0.7%, p = NS), and on day 28 (aspirin = 3.4 +/- 0.7%, NCX 4016 = 3.2 +/- 0.6%, p = NS). Maximal treadmill exercise induced an acute worsening of FMD in both groups at baseline (aspirin = -1.15%, nitroaspirin = -1.76%); after four weeks treatment, the impairment of FMD induced by exercise was still present in the aspirintreated group (-1.46%) while it was abolished in the NCX 4016-treated group (+0.79%, p = 0.038 vs. aspirin). Similarly, exercise induced an increase of plasma elastase and of sVCAM-1 which were not affected by aspirin while they were suppressed by NCX 4016. Maximal treadmill exercise induces a systemic arterial endothelial dysfunction in patients with intermittent claudication. A nitric oxide-donating aspirin, but not aspirin, prevents effort-induced endothelial dysfunction.
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PMID:Prevention by NCX 4016, a nitric oxide-donating aspirin, but not by aspirin, of the acute endothelial dysfunction induced by exercise in patients with intermittent claudication. 1733 96

We hypothesize that stimulation of Na+-K+-Cl+ cotransporter (NKCC1) causes Na+ overload that may lead to reversal of Na+-Ca2+ exchanger isoform 1 (NCX1) and ischemic neuronal damage. NCX1 protein expression and Ca2+ influx via reversal of NCX were decreased by approximately 70% in NCX1+/- neurons. Compared to NCX1+/+ neurons, NCX1+/- neurons exhibited significantly less cell death (approximately 30%) after 3 h oxygen and glucose deprivation (OGD) and 21 h reoxygenation. Additional neuroprotection was found in NCX1+/- neurons treated with NCX inhibitor KB-R7943. Moreover, expression of NCX1 protein was approximately 40% lower in NCX1+/- brains than in NCX1+/+ brains. However, there was no significant reduction in cerebral infarction in NCX1+/- mice following middle cerebral artery occlusion (MCAO). These data suggest that moderate reduction of NCX1 protein may be not enough to exert protection. We used small RNA-interference (siRNA) approach to further elucidate the role of NCX1 in ischemic cell damage. Efficacy of anti-NCX1 siRNA was tested in astrocytes and approximately 50% knockdown of NCX1 protein expression was achieved after 24-72 h transfection. Reduction in NCX1 protein expression was also found in brains of NCX1+/- mice after the siRNA injection. NCX1+/- mice treated with siRNA showed approximately 20% less MCAO-induced infarction, compared to NCX1+/- mice. Approximately 50% neuroprotection was detected in NKCC1+/-/NCX1+/- mice following MCAO. In conclusion, these data suggest that NCX1 plays an important role in ischemia/reperfusion-induced neuronal injury.
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PMID:Increased tolerance to ischemic neuronal damage by knockdown of Na+-Ca2+ exchanger isoform 1. 1744 70

Within the first 2 min of global brain ischemia, extracellular [K+] ([K+]o) increases above 60 mM and [Na+](o) drops to about 50 mM, indicating a massive K+ efflux and Na+ influx, a phenomenon known as anoxic depolarization (AD). Similar ionic shifts take place during repetitive peri-infarct depolarizations (PID) in the area penumbra in focal brain ischemia. The size of ischemic infarct is determined by the duration of AD and PID. However, the mechanism of cytosolic [Ca2+] ([Ca2+]c) elevation during AD or PID is poorly understood. Our data show that the exposure of cultured rat hippocampal CA1 neurons to AD-like conditions promptly elevates [Ca2+]c to about 30 microM. These high [Ca2+]c elevations depend on external Ca2+ and can be prevented by removing Na+ or by simultaneously inhibiting NMDA and AMPA/kainate receptors. These data indicate that [Ca2+]c elevations during AD result from Na+ influx via either NMDA or AMPA/kainate channels. The mechanism of the Na-dependent [Ca2+]c elevations may involve a reversal of plasmalemmal Na+/Ca2+ (NCX) and/or Na+/Ca2+ + K+ (NCKX) exchangers. KB-R7943, an NCX inhibitor, suppresses a fraction of the Na-dependent Ca2+ influx during AD. Therefore, Ca2+ influx via NCX and a KB-R7943-resistant pathway (possibly NCKX) is involved. Inhibition of the Na-dependent Ca2+ influx is likely to decrease ischemic brain damage. No drugs are known that are able to inhibit the KB-R7943-resistant component of Na-dependent Ca2+ influx during AD. The present data encourage development of such agents as potential therapeutic means to limit ischemic brain damage after stroke or heart attack.
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PMID:NCX and NCKX operation in ischemic neurons. 1744 79

Over the last few years, although extensive studies have focused on the relevant function played by the sodium-calcium exchanger (NCX) during focal ischemia, a thorough understanding of its role still remains a controversial issue. We explored the consequences of the pharmacological inhibition of this antiporter with conventional pharmacological approach, with the synthetic inhibitory peptide, XIP, or with an antisense strategy on the extent of brain damage induced by the permanent occlusion of middle cerebral artery (pMCAO) in rats. Collectively, the results of these studies suggest that ncx1 and ncx3 genes could be play a major role to limit the severity of ischemic damage probably as they act to dampen [Na+]i and [Ca2+]i overload. This mechanism seems to be normally activated in the ischemic brain as we found a selective upregulation of NCX1 and NCX3 mRNA levels in regions of the brain surviving to an ischemic insult. Despite this transcript increase, NCX1, NCX2, and NCX3 proteins undergo an extensive proteolytic degradation in the ipsilateral cerebral hemisphere. All together these results suggest that a rescue program centered on an increase NCX function and expression could halt the progression of the ischemic damage. On the basis of this evidence we directed our attention to the understanding of the transductional and transcriptional pathways responsible for NCX upregulation. To this aim, we are studying whether the brain isoform of Akt, Akt1, which is a downstream effector of neurotrophic factors, such as NGF can, in addition to affecting the other prosurvival cascades, also exert its neuroprotective effect by modulating the expression and activity of ncx1, ncx2, and ncx3 gene products.
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PMID:ncx1, ncx2, and ncx3 gene product expression and function in neuronal anoxia and brain ischemia. 1744 81

Sodium/calcium exchangers are neuronal plasma membrane transporters, which by coupling Ca2+ and Na+ fluxes, may play a relevant role in brain ischemia. The exchanger gene superfamily comprises two arms: the K+-independent (NCX) and K+-dependent (NCKX) exchangers. In the brain, three different NCX (NCX1, NCX2, NCX3) and three NCKX (NCKX2, NCKX3, NCKX4) family members have been described. Up to now, no sutides about the role played by NCKX proteins in cerebral ischemia have been published. The aim of the present study was to investigate the role of NCKX2 in an in vivo model of permanent middle cerebral artery occlusion (pMCAO). The role of this protein in the development of ischemic damage was assessed by knocking-down its expression with an antisense oligodeoxynucleotide (AS-ODN), intracerebroventricularly infused by an osmotic minipump for 48 h, starting from 24 h before pMCAO. The results showed that NCKX2 knocking-down by using antisense strategy increased the extent of the ischemic lesion. The results of this study suggest that NCKX2 could exert a neuroprotective effect during ischemic injury.
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PMID:Involvement of the potassium-dependent sodium/calcium exchanger gene product NCKX2 in the brain insult induced by permanent focal cerebral ischemia. 1744 91

During ischemia or hypoxia an increase in intracellular cytosolic Ca(2+) induces deleterious events but is also implicated in signaling processes triggered in such conditions. In MDCK cells (distal tubular origin), it was shown that mitochondria confer protection during metabolic inhibition (MI), by buffering the Ca(2+) overload via mitochondrial Na(+)-Ca(2+) exchanger (NCX). To further assess this process in cells of human origin, human cortical renal epithelial cells (proximal tubular origin) were subjected to MI and changes in cytosolic Ca(2+) ([Ca(2+)](i)), Na(+), and ATP concentrations were monitored. MI was accomplished with both antimycin A and 2-deoxyglucose and induced a 3.5-fold increase in [Ca(2+)](i), reaching 136.5 +/- 15.8 nM in the first 3.45 min. Subsequently [Ca(2+)](i) dropped and stabilized to 62.7 +/- 7.3 nM by 30 min. The first phase of the transient increase was La(3+) sensitive, not influenced by diltiazem, and abolished when mitochondria were deenergized with the protonophore carbonylcyanide p-trifluoromethoxyphenylhydrazone. The subsequent recovery phase was impaired in a Na(+)-free medium and weakened when the mitochondrial NCX was blocked with 7-chloro-5-(2-chlorophenyl)-1,5-dihydro-4,1-benzothiazepin-2(3H)-one (CGP-37157). Thus Ca(2+) entry is likely mediated by store-operated Ca(2+) channels and depends on energized mitochondria, whereas [Ca(2+)](i) recovery relied partially on the activity of mitochondrial NCX. These results indicate a possible mitochondrial-mediated signaling process triggered by MI, support the hypothesis that mitochondrial NCX has an important role in the Ca(2+) clearance, and overall suggest that mitochondria play a preponderant role in the regulation of responses to MI in human renal epithelial cells.
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PMID:Metabolic inhibition-induced transient Ca2+ increase depends on mitochondria in a human proximal renal cell line. 1752 66


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