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)

Although ischemia reperfusion has been shown to depress gene expression of the sarcoplasmic reticulum (SR) proteins, such as the ryanodine receptor, Ca2+-pump ATPase, phospholamban, and calsequestrin in the heart, the mechanisms of these changes are not understood. Given the occurrence of hypoxia and the lack of glucose during the ischemic phase, we investigated the effects of these factors on the cardiac SR gene expression. Isolated rat hearts perfused in the absence of oxygen and/or glucose for 30 min showed an increase in the expression of SR genes. However, perfusion of hearts for 60 min with normal oxygenated medium after 30 min of lack of both oxygen and glucose depressed the transcript levels for the SR proteins; these changes did not occur when hearts were deprived of either oxygen or glucose. The effect of intracellular Ca2+-overload, which occurs during reperfusion, was studied by using hearts perfused for 5 min with Ca2+-free medium and then reperfused for 30 min. Ca2+-depletion/repletion induced a dramatic decrease in the transcript levels of the SR genes. These results suggest that the lack of both oxygen and glucose during ischemia are necessary for reperfusion-induced depression in SR gene expression, possibly due to the occurrence of intracellular Ca2+-overload.
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PMID:Modulation of cardiac sarcoplasmic reticulum gene expression by lack of oxygen and glucose. 1164 Dec 57

We determined the effect of 9-hydroxyellipticine (9HE) on ryanodine receptor (RyR) and cardiac function after global ischemia in isolated rat hearts. The binding of [3H]-ryanodine in rabbit cardiac sarcoplasmic reticulum was displaced by 9HE in a biphasic manner corresponding to the two sites model with IC50 values of 6.1 microM and 55 mM. The increase of the intracellular Ca2+ concentration induced by caffeine in CHO cells expressing cardiac-type RyR was suppressed by 9HE in a concentration-dependent manner. Pretreatment of the heart with 9HE decreased the total duration of reperfusion-induced ventricular fibrillation (VF) and delayed the onset of VF. There was also a significant recovery of contractile force of ischemic hearts following 9HE. Unlike nifedipine, an L-type Ca2+-channel blocker, 9HE did not suppress the contraction of rat papillary muscles. Thus, 9HE exerts the cardioprotective effects against ischemia /reperfusion injury without changing hemodynamic indices.
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PMID:Cardioprotective effects of 9-hydroxyellipticine on ischemia and reperfusion in isolated rat heart. 1208 39

Elevated levels of free fatty acids (FFA) have been implicated in the pathogenesis of neuronal injury and death induced by cerebral ischemia. This study evaluated the effects of immunosuppressants agents, calcineurin inhibitors and blockade of endoplasmic reticulum (ER) calcium channels on free fatty acid formation and efflux in the ischemic/reperfused (I/R) rat brain. Changes in the extracellular levels of arachidonic, docosahexaenoic, linoleic, myristic, oleic and palmitic acids in cerebral cortical superfusates during four-vessel occlusion-elicited global cerebral ischemia were examined using a cortical cup technique. A 20-min period of ischemia elicited large increases in the efflux of all six FFAs, which were sustained during the 40 min of reperfusion. Cyclosporin A (CsA) and trifluoperazine, which reportedly inhibit the I/R elicited opening of a mitochondrial permeability transition (MPT) pore, were very effective in suppressing ischemia/reperfusion evoked release of all six FFAs. FK506, an immunosuppressant which does not directly affect the MPT, but is a calcineurin inhibitor, also suppressed the I/R-evoked efflux of FFAs, but less effectively than CsA. Rapamycin, a derivative of FK506 which does not inhibit calcineurin, did not suppress I/R-evoked FFA efflux. Gossypol, a structurally unrelated inhibitor of calcineurin, was also effective, significantly reducing the efflux of docosahexaenoic, arachidonic and oleic acids. As previous experiments had implicated elevated Ca(2+) levels in the activation of phospholipases with FFA formation, agents affecting endoplasmic reticulum stores were also evaluated. Dantrolene, which blocks the ryanodine receptor (RyR) channel of the ER, significantly inhibited I/R-evoked release of docosahexaenoic, arachidonic, linoleic and oleic acids. Ryanodine, which can either accentuate or block Ca(2+) release, significantly enhanced ischemia/reperfusion-elicited efflux of linoleic acid, with non-significant increases in the efflux of myristic, arachidonic, palmitic and oleic acids. Xestospongin C, an inhibitor of the inositol triphosphate (IP(3)R) channel, failed to affect I/R-evoked FFA efflux. Thapsigargin, an inhibitor of the Ca(2+)-ATPase ER uptake pump, elicited significant elevations in the efflux of myristic, arachidonic and linoleic acids, in the absence of ischemia. Collectively, the data suggest an involvement of both ER and mitochondrial Ca(2+) stores in the chain of events which lead to PLA(2) activation and FFA formation.
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PMID:Effects of immunosuppressants, calcineurin inhibition, and blockade of endoplasmic reticulum calcium channels on free fatty acid efflux from the ischemic/reperfused rat cerebral cortex. 1244 75

In the heart ischaemic conditions induce metabolic changes known to have profound effects on Ca(2+) signalling during excitation-contraction coupling. Ischaemia also affects the redox state of the cell. However, the role of cytosolic redox couples, such as the NADH/NAD(+) redox system, for the regulation of Ca(2+) homeostasis has remained elusive. We studied the effects of NADH and NAD(+) on sarcoplasmic reticulum (SR) Ca(2+) release in permeabilized rat ventricular myocytes as well as on Ca(2+) uptake by SR microsomes and ryanodine receptor (RyR) single channel activity. Exposure of permeabilized myocytes to NADH (2 mm; [Ca(2+)](cyt)= 100nm) decreased the frequency and the amplitude of spontaneous Ca(2+) sparks by 62% and 24%, respectively. This inhibitory effect was reversed by NAD(+) (2 mm) and did not depend on mitochondrial function. The inhibition of Ca(2+) sparks by NADH was associated with a 52% decrease in SR Ca(2+) load. Some of the effects observed with NADH may involve the generation of superoxide anion (O(2)(-).) as they were attenuated to just a transient decrease of Ca(2+) spark frequency by superoxide dismutase (SOD). O(2)(-). generated in situ from the xanthine/xanthine oxidase reaction caused a slowly developing decrease of Ca(2+) spark frequency and SR Ca(2+) load by 44% and 32%, respectively. Furthermore, in studies with cardiac SR microsomes NADH slowed the rate of ATP-dependent Ca(2+) uptake by 39%. This effect also appeared to depend on O(2)(-). formation. Single channel recordings from RyRs incorporated into lipid bilayers revealed that NADH (2 mm) inhibited the activity of RyR channels by 84%. However, NADH inhibition of RyR activity was O(2)(-).-independent. In summary, an increase of the cytoplasmic NADH/NAD(+) ratio depresses SR Ca(2+) release in ventricular cardiomyocytes. The effect appears to be mediated by direct NADH inhibition of RyR channel activity and by indirect NADH inhibition (O(2)(-). mediated) of SR Ca(2+)-ATPase activity with a subsequent decrease in SR Ca(2+) content.
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PMID:Effects of cytosolic NADH/NAD(+) levels on sarcoplasmic reticulum Ca(2+) release in permeabilized rat ventricular myocytes. 1472 8

During cardiac filling, the relative contribution of distension of interstitial collagen, of distension of cytoskeletal proteins, and of low-grade diastolic cross-bridge cycling in the generation of diastolic left ventricular (LV) pressure remains unclear. In failing myocardium, interstitial collagen deposition and cross-linking are augmented. This increase in collagen deposition is accompanied by expression of a stiffer isoform of titin in the cardiomyocytes. Higher diastolic stiffness of failing myocardium is therefore not necessarily related to increased interstitial collagen content. Moreover, phosporylation of titin by protein kinase A and G, and inhibition of titin-actin interaction by cytosolic calcium allow for dynamic modulation of its diastolic tension generation and could account for acute shifts of myocardial distensibility. Acute shifts of myocardial distensibility, as occur in hypertrophy or in demand ischemia, have usually been attributed to a diastolic resurgence of cross-bridge interaction. In hypertrophied and failing myocardium, the recent demonstrations of diastolic calcium release from the ryanodine receptor, of deficient diastolic calcium removal from the cytosol, and of enhanced myofilamentary calcium sensitivity support residual diastolic cross-bridge interaction. In demand ischemia, the role of calcium overload in the reduction of diastolic LV distensibility is less clear because of correction of the reduced diastolic LV distensibility by quick stretches but not by a calcium desensitizer. Simultaneous imposition in animal models of multiple molecular changes involving interstitial, cytoskeletal, and myofilamentary proteins could elucidate their relative importance for myocardial stiffness and lead to selective correction of diastolic LV dysfunction as a novel mode of heart-failure therapy.
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PMID:Matrix, cytoskeleton, or myofilaments: which one to blame for diastolic left ventricular dysfunction? 1599 Nov 55

We hypothesized that activation of heat shock protein 70 (HSP70) by preconditioning, which is known to confer delayed cardioprotection, attenuates the impaired handling of Ca(2+) at multiple sites. To test the hypothesis, we determined how the ryanodine receptor (RyR), sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA), and Na(+)/Ca(2+) exchanger (NCX) handled Ca(2+) in rat ventricular myocytes preconditioned with a kappa-opioid receptor agonist, U50488H (UP), followed by blockade of HSP70 with a selective antisense oligonucleotide and subsequently subjected to simulated ischemia. We determined the following: 1) the Ca(2+) transients induced by electrical stimulation and caffeine, which provide the overall picture of Ca(2+) homeostasis; 2) expression of RyR, SERCA, and NCX; and 3) Ca(2+) fluxes via NCX by the use of (45)Ca(2+) in the rat ventricular myocyte. We found that UP increased the activity of RyR, SERCA, and NCX and the expression of RyR and SERCA. These effects led to increases in the release of Ca(2+) from the sarcoplasmic reticulum via RyR and in the removal of Ca(2+) from the cytoplasm by reuptake of Ca(2+) to the SR via SERCA and by extrusion of Ca(2+) out of the cell via NCX. UP also reduced mitochondrial Ca(2+) accumulation. All of the effects of UP were either abolished or significantly attenuated by blockade of HSP70 synthesis with a selective antisense oligonucleotide. The results are evidence that activation of HSP70 by preconditioning improves the ischemia-impaired Ca(2+) homeostasis at multiple sites in the heart, which may be responsible, at least partly, for attenuated Ca(2+) overload, improved recovery in contractile function, and cardioprotection.
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PMID:Further study on the role of HSP70 on Ca2+ homeostasis in rat ventricular myocytes subjected to simulated ischemia. 1620 97

We investigated whether A(1) adenosine receptor stimulation affects expression of genes involved in calcium homeostasis, including sarcolemmal L-type Ca(2+) channel, Na(+)/Ca(2+) exchanger, sarcoplasmic reticulum (SR) Ca(2+)-ATPase, phospholamban, or ryanodine receptor. Three models of A(1) stimulation were used: i) an acute model, i.e. isolated perfused rat hearts treated for 120 min with 15 nM R-phenylisopropyladenosine (R-PIA), an A(1) receptor agonist; ii) a subacute model, i.e. rats treated with 1.5 mg/kg R-PIA e.v. and sacrificed after 24 h; iii) a transgenic model, i.e. mice overexpressing A(1) adenosine receptors. In all models gene expression was determined by RT-PCR, and oxalate-supported Ca(2+) uptake, representing SR Ca(2+) uptake, was measured in the crude homogenate. Significant increase in the expression of the phospholamban gene was observed in each model of A(1) stimulation, while the expression of the other four genes was not significantly modified. In the acute model, SR Ca(2+) uptake was unaffected, however in the subacute and transgenic models uptake rate was significantly reduced. In parallel experiments, hearts obtained from the subacute model demonstrated a significant reduction in irreversible tissue injury from 30 min of ischemia and 120 min of reperfusion. Increased resistance to ischemia has already been reported also in our transgenic model. In conclusion, A(1) adenosine receptor stimulation up-regulates phospholamban gene expression, which leads within 24 h to a reduced rate of SR Ca(2+) uptake. Changes in Ca(2+) homeostasis might contribute to the delayed cardioprotective effect of adenosine.
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PMID:Effects of A1 adenosine receptor stimulation on the expression of genes involved in calcium homeostasis. 1621 64

Human hibernating myocardium (HHM) is characterized by reversible contractile dysfunction during chronic ischemia. A disturbed calcium-homeostasis is a decisive factor for reduced functional capacity in heart diseases. We therefore investigated calcium-handling proteins in HHM. In 12 patients suffering from multi-vessel coronary artery disease and contractile dysfunction with indication for bypass surgery, HHM was detected preoperatively by thallium scintigraphy, radionuclide ventriculography and dobutamine echocardiography. Transmural biopsies of these regions were taken and analyzed by immunohistochemistry and electron microscopy. Furthermore, SR-calcium ATPase (SERCA2a), phospholamban (PLN), the phosphorylated forms of PLN (PLN-Ser16, PLN-Thr17) as well as sodium-calcium exchanger (NCX) and ryanodine receptor (RyR2) were investigated by RT-PCR and Western-blotting. Additionally, SERCA2a activity was measured by an enzyme-coupled assay. In all patients complete functional recovery could be documented 3 months after revascularization by repeating all preoperative investigations. In HHM maximal SERCA2a activity was significantly reduced (HHM: 424.5 +/- 33.9, control: 609.0 +/- 48.5 nmol ATP mg protein(-1) min(-1), p <or= 0.05), whereas SERCA2a protein levels were unchanged. mRNA levels (HHM: 1.36 +/- 0.08 vs. control: 0.78 +/- 0.04, p <or= 0.05) and protein amount (HHM:1.67 +/- 0.14 vs. control: 1.00 +/- 0.04, p <or= 0.05) of PLN (A1) were increased resulting in an increased PLN:SERCA2a-ratio. PLN-Ser16 (HHM: 0.60 +/- 0.08 vs. control: 1.00 +/- 0.11, p <or= 0.05) and PLN-Thr17 (HHM: 0.63 +/- 0.11 vs. control: 1.00 +/- 0.06, p <or= 0.05) phosphorylation was significantly decreased. RyR2 and NCX showed no significant alteration. In HHM a decreased activity of SERCA2a due to an impaired phosphorylation of PLN contributes to contractile dysfunction. The increase in the relative ratio of PLN/SERCA2a leads to a decreased calcium affinity of SERCA2a.
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PMID:Reduced sarcoplasmic reticulum Ca2+ -ATPase activity and dephosphorylated phospholamban contribute to contractile dysfunction in human hibernating myocardium. 1631 12

Previously we have shown that the biphasic efflux of mitochondrial protein cytochrome c to cytoplasm is one of the important events of the delayed postichemic neuronal death. We concluded that early and transient appearance of cytochrome c in cytoplasm of cells recovering after ischemia was decisive for initiation of the pathological signaling cascade leading to neuronal death, but the precise mechanism remained unknown. In vitro cytochrome c was identified as a messenger that coordinates mitochondrial-endoplasmatic reticulum interactions that drive apoptosis. Here we show that in vivo cytochrome c interacts with inositol (1,4,5) trisphosphate receptor type 1 in gerbil hippocampus subjected to transient brain ischemia and short reperfusion. Moreover, cytochrome c binds also to ryanodine receptor type 2, the role of which in postischemic neuronal death is suggested. The complexes could be coimmunoprecipitated by antibodies against any of the two proteins. Our data verified that the mechanism observed in vitro applies to the pathological in vivo situation.
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PMID:Cytochrome c binds to inositol (1,4,5) trisphosphate and ryanodine receptors in vivo after transient brain ischemia in gerbils. 1651 19

Intracellular concentrations of redox-active molecules can significantly increase in the heart as a result of activation of specific signal transduction pathways or the development of certain pathophysiological conditions. Changes in the intracellular redox environment can affect many cellular processes, including the gating properties of ion channels and the activity of ion transporters. Because cardiac contraction is highly dependent on intracellular Ca(2+) levels ([Ca(2+)](i)) and [Ca(2+)](i) regulation, redox modification of Ca(2+) channels and transporters has a profound effect on cardiac function. The sarcoplasmic reticulum (SR) Ca(2+) release channel, or ryanodine receptor (RyR), is one of the well-characterized redox-sensitive ion channels in the heart. The redox modulation of RyR activity is mediated by the redox modification of sulfhydryl groups of cysteine residues. Other key components of cardiac excitation-contraction (e-c) coupling such as the SR Ca(2+) ATPase and L-type Ca(2+) channel are subject to redox modulation. Redox-mediated alteration of the activity of ion channels and pumps is directly involved in cardiac pathologies such as ischemia-reperfusion injury. Significant bursts of reactive oxygen species (ROS) generation occur during reperfusion of the ischemic heart, and changes in the activity of the major components of [Ca(2+)](i) regulation, such as RyR, Na(+)-Ca(2+) exchange and Ca(2+) ATPases, are likely to play an important role in ischemia-related Ca(2+) overload. This article summarizes recent findings on redox regulation of cardiac Ca(2+) transport systems and discusses contributions of this redox regulation to normal and pathological cardiac function.
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PMID:Redox regulation of cardiac calcium channels and transporters. 1658 Oct 43


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