UMLS:C0022116 - FACTA Search

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

Oxidative stress is a recognized pathogenic factor in ischemia/reperfusion injury (IRI). Iron induced generation of reactive oxygen species (ROS) in vitro reduces both the Na+K+-ATPase activity and Na+-Ca2+ exchanger of synaptosomal membranes, concomitantly with alteration of physical state of membranes. Oxidative insult also leads to the loss of ability of endoplasmic reticular membranes (ER) to sequester Ca2+ as well as to the increase of Ca2+ permeability. Furthermore, ROS induces both lipid peroxidation and lipid-independent modifications of membrane proteins. Acute in vivo ischemia alters kinetic parameters of Na+K+-ATPase affecting mainly the dephosphorylation step of ATPase cycle with parallel changes of Na+-Ca2+ exchanger and alterations of physical membrane environment. Subsequent reperfusion after ischemia is associated with decrease of immuno signal for PMCA 1 isoform in hippocampus. In addition, incubation of non-ischemic membranes with cytosol from ischemic hippocampus decreases level of PMCA 1 in non-ischemic tissues. Loss of PMCA 1 protein is partially protected both by calpain- and by non-specific protease inhibitors which suggest possible activation of proteases in the reperfusion period. On the other hand, ischemia does not affect the level of Ca2+ pump (SERCA 2b) and calreticulin of intracellular Ca2+ stores. However, IRI resulted in a decrease of IP3 receptor I and altered active Ca2+ accumulation into the ER. A non-specific alteration of physical properties of total membranes such as the oxidative modifications of proteins as well as the content of lipoperoxidation products can also be detected after IRI. ROS can alter physical and functional properties of neuronal membranes. We discuss our results suggesting that ischemia-induced disturbation of ion transport systems may participate in or follow delayed death of neurons after ischemia.
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PMID:Ion transport systems as targets of free radicals during ischemia reperfusion injury. 1216 23

Increase in free intracellular calcium [Ca 2+]i plays a crucial role in cardiomyocyte ischemic injury. Here we demonstrate that overexpression of the sarcoplasmic-reticulum stress-protein Grp94 reduces myocyte necrosis due to calcium overload or simulated ischemia. Selective three- to eightfold Grp94 increase, with no change in Grp78 or calreticulin amount, was achieved by stable transfection of skeletal C2C12 and cardiac H9c2 muscle cells. After exposure to the calcium ionophore A23187, LDH release from five different Grp94-overexpressing clones of either C2C12 and H9c2 origin was significantly lower than that of control ones and [Ca 2+]i increase was significantly delayed. The number of necrotic cells, evaluated by propidium iodide uptake, was reduced when cells from the Grp94-overexpressing H9c2 clone were exposed to conditions simulating ischemia. Experiments performed in neonatal rat cardiomyocytes co-transfected with grp94 and the green fluorescent protein (GFP) cDNAs validated the protective effect of Grp94 overexpression. A lower percentage of propidium-iodide positive/GFP-fluorescent myocytes co-expressing exogenous Grp94, with respect to myocytes expressing GFP alone, was observed after exposure to either A23187 (6.6% vs. 14.0%, respectively) or simulated ischemia (8.5% vs. 17.7%, respectively). In conclusion, the selective increase in Grp94 protects cardiomyocytes from both ischemia and calcium overload counteracting [Ca 2+]i elevations.
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PMID:Overexpression of the stress protein Grp94 reduces cardiomyocyte necrosis due to calcium overload and simulated ischemia. 1267 Aug 79

Both in vivo and cultured cardiomyocyte experiments were performed to investigate the alteration of expression of calreticulin (CRT) during the delayed cardioprotection induced by hypoxic preconditioning (HPC) and the intracellular signal transduction mechanisms of the alteration. (1) Wistar rats were randomly divided into three groups: sham operation group (Sham), myocardial infarction (MI) group induced by left coronary artery ligation and HPC+MI group (4-hour HPC 24 h before MI). Twenty-four hours, 14 d and 28 d after left coronary artery ligation, myocardial function, infarction size and the area at risk were measured. Western blot was used to detect the expression of CRT, the activity of p38 mitogen-activated protein kinase (MAPK) and stress-activated protein kinase (SAPK). (2) Cultured cardiomyocytes from neonatal Sprague-Dawley (SD) rat were divided into six groups: hypoxia/reoxygenation (H/R), HPC, HPC+H/R, p38 MAPK inhibitor SB203580+HPC+H/R (SB+HPC+H/R), SAPK inhibitor SP600125+HPC+H/R (SP+HPC+H/R) and control. Survival rate and apoptosis rate of cardiomyocytes 6 h after H/R and activities of lactate dehydrogenase (LDH) in culture medium in each group were measured. Western blot was used to detect the expression of CRT and activities of p38 MAPK and SAPK. The results are as follows: (1) During in vivo experiment, compared with MI group, HPC significantly improved +dp/dt(max) and -dp/dt(max), reduced infarction size and the area at risk. HPC dramatically changed the expression of CRT. CRT expression in HPC+MI group was 206% of that in MI group (P<0.05) 24 h after infarction, especially in the area at risk. However, 28 d after operation, the expression of CRT decreased by 57%. Correlation analysis indicated a positive correlation between CRT expression and myocardial function (r=0.9867, P<0.05), and negative correlation between CRT expression and infarction size (r=-0.9709, P<0.05). (2) In cultured cardiomyocytes, HPC attenuated cell injury induced by H/R. CRT expression increased moderately to 222% of control (P<0.05) during HPC, but increased dramatically to 503% of control (P<0.05) after H/R. HPC reduced H/R-induced CRT up-regulation to 56% of that in H/R group (P<0.05). Correlation analysis indicated that CRT expression induced by HPC had a positive correlation with p38 MAPK activity (r=0.9021, P<0.05), but a negative correlation with SAPK activity (r=-0.8211, P<0.05). Both in vivo and in vitro results indicate that HPC protects myocardium from ischemia or H/R injury. p38 MAPK is possibly involved in the up-regulation of CRT induced by HPC, while SAPK has a negative influence.
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PMID:[Calreticulin expression increases during delayed cardioprotection induced by hypoxic preconditioning]. 1717 88

The protective mechanisms of hypoxic preconditioning (HPC) involve the mitigation of cellular calcium overload in cardiomyocytes. The sarcoplasmic reticulum (SR) chaperone calreticulin (CRT) plays an important role in regulating calcium homeostasis and is upregulated by HPC. The goal of this study was to show whether the late cardioprotection of HPC is mediated by calreticulin upregulation and to demonstrate whether the calreticulin induction is mediated by p38 MAPK phosphorylation. Hypoxic preconditioning was induced by hypoxemic hypoxic exposure by a 24-h period of normoxic reoxygenation before undergoing LAD occlusion in rats or hypoxia/reoxygenation (H/R) in cardiomyocytes. Ca uptake and release of the SR vesicles was determined by use of Ca and the Millipore filtration technique. Western blotting analysis was used to detect calreticulin expression and activity of p38 MAPK. Hypoxic preconditioning induced calreticulin upregulation and attenuated H/R injury in neonatal cardiomyocytes and myocardial ischemia injury by increasing calcium uptake and reducing calcium release in SR. Hearts from the HPC group were more resistant to sustained ischemia and had much stronger phosphorylation of p38 MAPK than sham operation. Inhibition of p38 MAPK with SB202190 (a selective p38 MAPK inhibitor) abolished the calreticulin upregulation and cardioprotection by HPC. Hypoxic preconditioning upregulates calreticulin expression through a p38 MAPK signaling pathway and protects cardiomyocytes from H/R (and ischemia) injury.
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PMID:Hypoxic preconditioning induces delayed cardioprotection through p38 MAPK-mediated calreticulin upregulation. 1743 64

The present study was aimed to investigate the effect of ischemic postconditioning (I-postC) on ischemia/reperfusion (I/R) injury and whether calreticulin (CRT) is involved in its intracellular signal transduction both in vivo and in cultured skeletal muscle cells. I/R injury in the right hind limb of healthy male Wistar rats was induced by clamping the right femoral artery, and the rats were randomly divided into 3 groups (n=16): I/R group (4-hour ischemia/12- or 24-hour reperfusion), ischemic preconditioning (IPC) group (3 cycles of 1-minute ischemia/1-minute reperfusion) and I-postC group (3 cycles of 5-minute reperfusion/5-minute ischemia). The left hind limb was used as control. Lactate dehydrogenase (LDH) activity in blood plasma, wet/dry weight ratio (W/D) and ultramicrostructure of skeletal muscle were detected 12 h or 24 h after reperfusion. Cultured skeletal muscle cells from neonatal Sprague-Dawley (SD) rat were divided into 6 groups: hypoxia/reoxygenation (H/R) group, hypoxic postconditioning (H-postC) group, hypoxic preconditioning (HPC) group, cyclosporine A (CsA) + H-postC group, CsA + H/R group and control group. H/R was produced by 2-hour hypoxia/24-hour reoxygenation. The survival rate and apoptotic rate of skeletal muscle cells in each group were measured. Western blot was used to detect the expressions of CRT and calcineurin (CaN). The results were as follows: (1) During in vivo experiment, compared with I/R, I-postC significantly decreased LDH activity and W/D, attenuated the ultramicrostructure injury of skeletal muscle and the apoptosis of nucleolus. 12 h and 24 h after reperfusion, compared with that in I/R group, the expression of CRT in I-postC group increased by 439% and 102%, respectively (P<0.05), and the expression of CaN increased by 196% and 63%, respectively (P<0.05). Correlation analysis indicated a positive correlation between CRT and CaN expressions (r=0.865, P<0.01). (2) In cultured skeletal muscle cells, H-postC attenuated cell injury induced by H/R. Compared with those in H/R group, CRT and CaN expressions in H-postC increased by 31.8% (P<0.05) and 6.02%, respectively. The protection of H-postC and CaN up-regulation were eliminated when CsA, the inhibitor of CaN, was added before H-postC. Both in vivo and in vitro results indicate that I-postC, similar as IPC, can protect the skeletal muscle against I/R injury, and its effects may be mediated by CRT and CaN up-regulation. The inhibition of CaN expression may also attenuate the protective effects of I-postC.
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PMID:[Calreticulin is involved in ischemic postconditioning-induced attenuation of ischemia/reperfusion injury in rat skeletal muscle]. 1794 Jul 5

Sarcolemmal Na(+)/H(+) exchanger (NHE) activity, which is provided by the NHE isoform 1 (NHE1), has been implicated in ischemia/reperfusion-induced myocardial injury in animal models and humans, on the basis of studies with pharmacological NHE1 inhibitors. We generated a transgenic (TG) mouse model with cardiac-specific over-expression of NHE1 to determine whether this would be sufficient to increase myocardial susceptibility to ischemia/reperfusion-induced injury. TG mouse hearts exhibited increased sarcolemmal NHE activity and normal morphology and function. Surprisingly, they also showed reduced susceptibility to ischemia/reperfusion-induced injury, as reflected by improved functional recovery and smaller infarcts. Such protection was sustained in the presence of NHE1 inhibition with zoniporide, indicating a mechanism that is independent of sarcolemmal NHE activity. Immunoblot analysis revealed accumulation of immature NHE1 protein as well as marked upregulation of both cytoprotective (78/94 kDa glucose-regulated proteins, calreticulin, protein disulfide isomerase) and pro-apoptotic (C/EBP homologous protein) components of the endoplasmic reticulum (ER) stress response in TG myocardium. With increasing age, NHE1 TG mice exhibited increased myocyte apoptosis, developed left ventricular contractile dysfunction, underwent cardiac remodelling and died prematurely. Our findings indicate that: (1) Cardiac-specific NHE1 over-expression induces the ER stress response in mouse myocardium, which may afford protection against ischemia/reperfusion-induced injury despite increased NHE activity; (2) Ageing NHE1 TG mice exhibit myocyte apoptosis, cardiac remodelling and failure, likely as a result of sustained ER stress; (3) The pluripotent effects of the ER stress response may confound studies that are based on the chronic over-expression of complex proteins in myocardium.
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PMID:Paradoxical resistance to myocardial ischemia and age-related cardiomyopathy in NHE1 transgenic mice: a role for ER stress? 1902 22

Adiponectin is a fat-derived plasma protein that has cardioprotective roles in obesity-linked diseases. Because cyclooxygenase 2 (COX-2) is an important modulator of endothelial function, we investigated the possible contribution of COX-2 to adiponectin-mediated vascular responses in a mouse hind limb model of vascular insufficiency. Ischemic insult increased COX-2 expression in endothelial cells of wild-type mice, but this induction was attenuated in adiponectin knockout mice. Ischemia-induced revascularization was impaired in mice in which the Cox-2 gene is deleted in Tie2-Cre-expressing cells. Adenovirus-mediated overexpression of adiponectin enhanced COX-2 expression and revascularization of ischemic limbs in control mice, but not in targeted Cox-2-deficient mice. In cultured endothelial cells, adiponectin protein increased COX-2 expression, and ablation of COX-2 abrogated the adiponectin-stimulated increases in endothelial cell migration, differentiation, and survival. Ablation of calreticulin (CRT) or its adaptor protein CD91 diminished adiponectin-stimulated COX-2 expression and endothelial cell responses. These observations provide evidence that adiponectin promotes endothelial cell function through CRT/CD91-mediated increases in COX-2 signaling. Thus, disruption of the adiponectin-COX-2 regulatory axis in endothelial cells could participate in the pathogenesis of obesity-related vascular diseases.
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PMID:Adiponectin promotes revascularization of ischemic muscle through a cyclooxygenase 2-dependent mechanism. 1939 82

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

Excessive endoplasmic reticulum stress (ERS) disrupts protein translation, protein folding, and calcium homeostasis and may contribute to ischemia-reperfusion injury. Saponins extracted from the stems and leaves of Panax quinquefolium (PQS) protect rat myocardium against ischemia-reperfusion injury, but it is not known if suppression of ERS contributes to cardioprotection. Neonatal rat cardiomyocytes were subjected to hypoxia-reoxygenation (H-R) in the presence of PQS or vehicle. Cell injury and apoptosis were assayed by trypan blue exclusion, lactate dehydrogenase activity, and flow cytometry. In addition, reverse transcriptase-polymerase chain reaction and Western blotting were used to examine mRNA and protein expression of the ERS-related proteins glucose-regulated protein 78, calreticulin, CCAAT/enhancer-binding protein homologous protein, and caspase-12, as well as the apoptosis-associated proteins Bax and Bcl-2. We confirmed that PQS protects cardiomyocytes from H-R-induced injury and apoptotic cell death. Furthermore, PQS suppressed H-R-induced excessive ERS, as evidenced by reduced caspase 12 activation and decreased glucose-regulated protein 78, calreticulin, and CCAAT/enhancer-binding protein homologous protein overexpression. These results indicated that PQS could alleviate H-R injury of cardiomyocytes, which would be probably related to inhibiting excessive ERS induced by H-R.
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PMID:Panax quinquefolium saponins reduce myocardial hypoxia-reoxygenation injury by inhibiting excessive endoplasmic reticulum stress. 2208 6

A nodal regulator of endoplasmic reticulum stress is the transcription factor, ATF6, which is activated by ischemia and protects the heart from ischemic damage, in vivo. To explore mechanisms of ATF6-mediated protection in the heart, a whole-genome microRNA (miRNA) array analysis of RNA from the hearts of ATF6 transgenic (TG) mice was performed. The array identified 13 ATF6-regulated miRNAs, eight of which were downregulated, suggesting that they could contribute to increasing levels of their mRNAs. The down-regulated miRNAs, including miR-455, were predicted to target 45 mRNAs that we had previously shown by microarray analysis to be up-regulated by ATF6 in the heart. One of the miR-455 targets was calreticulin (Calr), which is up-regulated in the pathologic heart, where it modulates hypertrophic growth, potentially reducing the impact of the pathology. To validate the effects of miR-455, we showed that Calr protein was increased by ATF6 in mouse hearts, in vivo. In cultured cardiac myocytes, treatment with the ER stressor, tunicamycin, or with adenovirus encoding activated ATF6 decreased miR-455 and increased Calr levels, consistent with the effects of ATF6 on miR-455 and Calr, in vivo. Moreover, transfection of cultured cardiac myocytes with a synthetic precursor, premiR-455, decreased Calr levels, while transfection with an antisense, antimiR-455, increased Calr levels. The results of this study suggest that ER stress can regulate gene expression via ATF6-mediated changes in micro-RNA levels. Moreover, these findings support the hypothesis that ATF6-mediated down-regulation of miR-455 augments Calr expression, which may contribute to the protective effects of ATF6 in the heart.
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PMID:Regulation of microRNA expression in the heart by the ATF6 branch of the ER stress response. 2232 32

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