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)

Heme oxygenase-1 (HO-1) overexpression protects against tissue injury in many inflammatory processes, including ischemia/reperfusion injury (IRI). This study evaluated whether genetically decreased HO-1 levels affected susceptibility to liver IRI. Partial warm ischemia was produced in hepatic lobes for 90 min followed by 6 h of reperfusion in heterozygous HO-1 knockout (HO-1(+/-)) and HO-1(+/+) wild-type (WT) mice. HO-1(+/-) mice demonstrated reduced HO-1 mRNA/protein levels at baseline and postreperfusion. This corresponded with increased hepatocellular damage in HO-1(+/-) mice, compared with WT. HO-1(+/-) mice revealed enhanced neutrophil infiltration and proinflammatory cytokine (TNF-alpha, IL-6, and IFN-gamma) induction, as well as an increase of intrahepatic apoptotic TUNEL(+) cells with enhanced expression of proapoptotic genes (Bax/cleaved caspase-3). We used cobalt protoporphyrin (CoPP) treatment to evaluate the effect of increased baseline HO-1 levels in both WT and HO-1(+/-) mice. CoPP treatment increased HO-1 expression in both animal groups, which correlated with a lower degree of hepatic damage. However, HO-1 mRNA/protein levels were still lower in HO-1(+/-) mice, which failed to achieve the degree of antioxidant hepatoprotection seen in CoPP-treated WT. Although the baseline and postreperfusion HO-1 levels correlated with the degree of protection, the HO-1 fold induction correlated instead with the degree of damage. Thus, basal HO-1 levels are more critical than the ability to up-regulate HO-1 in response to the IRI and may also predict the success of pharmacologically induced cytoprotection. This model provides an opportunity to further our understanding of HO-1 in stress defense mechanisms and design new regimens to prevent IRI.
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PMID:Basal rather than induced heme oxygenase-1 levels are crucial in the antioxidant cytoprotection. 1698 15

Ischemia and reperfusion injury (IRI) is the main etiology of acute renal failure in native and transplanted kidneys. In the transplantation field, immunosuppressive drugs may play an additional role in acute graft dysfunction. Rapamycin may impair renal regeneration post IRI. Heme oxygenase 1 (HO-1) is a protective gene with anti-inflammatory and anti-apoptotic actions. We investigated whether HO-1 played a role in rapamycin-induced renal dysfunction in an established model of IRI. Rapamycin (3 mg/kg) was administered to mice before being subjected to 45 min of ischemia. Animals subjected to IRI presented with impaired renal function that peaked at 24 h (2.05+/-0.23 mg/dl), decreasing thereafter. Treatment with rapamycin caused even more renal dysfunctions (2.30+/-0.33 mg/dl), sustained up to 120 h after reperfusion (1.54+/-0.4 mg/dl), when compared to the control (0.63+/-0.09 mg/dl, P<0.05). Rapamycin delayed tubular regeneration that was normally higher in the control group at day 5 (68.53+/-2.30 vs 43.63+/-3.11%, P<0.05). HO-1 was markedly upregulated after IRI and its expression was even enhanced by rapamycin (1.32-fold). However, prior induction of HO-1 by cobalt protoporphyrin improved the renal dysfunction imposed by rapamycin, mostly at later time points. These results demonstrated that rapamycin used in ischemic-injured organs could also negatively affect post-transplantation recovery. Modulation of HO-1 expression may represent a feasible approach to limit rapamycin acute toxicity.
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PMID:The role of heme oxygenase 1 in rapamycin-induced renal dysfunction after ischemia and reperfusion injury. 1700 13

The effect of acute renal failure (ARF) induced by ischemia/reperfusion (I/R) of rat kidney on the expression of organic anion transporters (OATs) was examined. The level of serum indoxyl sulfate (IS), a uremic toxin and substrate of OATs in renal tubules, shows a marked increase with the progression of ARF. However, this increase was significantly attenuated by ingestion of cobalt. The level of mRNA and protein of both rOAT1 and rOAT3 were markedly depressed in the ischemic kidney. The uptake of p-aminohippuric acid (PAH) and estrone sulfate (ES) by renal slices of ischemic rats was significantly reduced compared to control rats. Renal slices taken from ischemic rats treated with cobalt displayed significantly elevated levels of ES uptake. Cobalt intake did not affect PAH uptake, indicating the functional restoration of rOAT3 but not rOAT1. The expression of Na(+)/K(+)-ATPase was markedly depressed in the ischemic kidney, suggesting that the inward Na(+) gradient in renal tubular cells had collapsed, thereby reducing the outward gradient of alpha-ketoglutarate, a driving force of both rOATs. The decreased expression of Na(+)/K(+)-ATPase was significantly restored by cobalt treatment. Our results suggest that the downregulation of renal rOAT1 and rOAT3 could be responsible for the increase in serum IS level of ischemic rats. Cobalt treatment has a significant protective effect on ischemia-induced ARF, being accompanied by the restoration of rOAT3 and/or Na(+)/K(+)-ATPase function.
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PMID:Downregulation of organic anion transporters in rat kidney under ischemia/reperfusion-induced acute [corrected] renal failure. 1724 93

We have examined the protective effect and mechanisms of heme oxygenase-1 (HO-1) induction in rat liver model of ex vivo cold ischemia preservation using cobalt protoporphyrin (CoPP) as HO-1 inducer and zinc protoporphyrin (ZnPP) as HO-1 inhibitor. There was a decrease in both aspartate transaminase and lactate dehydrogenase activities and in malondialdehyde level in liver of the CoPP-treated group compared with controls (p < 0.05). In the CoPP-treated rats, the histological signs of reperfusion injury were much lower than in control. Up-regulation of HO-1 expression was also associated with reduced levels of tumor necrosis factor alpha and interleukin-6. Markedly fewer apoptotic liver cells (determined by TUNEL assay) could be detected in CoPP-treated group compared with the control group. These protective effects were prevented by administration of ZnPP. In conclusion, induction of HO-1 provides protection against liver injury during cold ischemia preservation and improves the preservation of liver graft. The mechanisms underlying these beneficial effects include reduction of oxidative injury and of inflammatory response and prevention of apoptosis.
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PMID:Induction of heme oxygenase-1 improves cold preservation effect of liver graft. 1757 9

T(4) activation into T(3) is catalyzed by type 2 deiodinase (D2) in the brain. The rapid induction of D2 in astrocytes by transient brain ischemia has prompted us to explore the effects of hypoxia on D2 in cultures of astrocytes. Hypoxia (2.5% O(2)) of cultured astrocytes increased D2 activity, alone or in association with agents stimulating the cAMP pathway. Hypoxia had no effect on D2 mRNA accumulation. Cycloheximide did not block the effect of hypoxia on D2 activity and D2 half-life was enhanced under hypoxia demonstrating a posttranslational action of hypoxia. Furthermore, the D2 activity increase by hypoxia was not additive with the increase promoted by the proteasome inhibitor carbobenzoxy-L-leucyl-L-leucyl-L-leucinal (MG132). This strongly suggests that hypoxia leads to stabilization of D2 by slowing its degradation by the proteasome pathway. Hypoxia, in contrast to MG132, did not block the T(4)-induced D2 inactivation. A contribution of prolyl hydroxylase to the hypoxia effects on D2 was also suggested on the basis of increased D2 activity after addition of different prolyl hydroxylase inhibitors (cobalt chloride, desferrioxamine, dimethyloxalylglycine, dimethylsuccinate). Specific inhibitors of ERK, p38 MAPK, or phosphatidylinositol 3-kinase pathways were without any effect on hypoxia-increased D2 activity, eliminating their role in the effects of hypoxia. Interestingly, diphenyleneiodonium, an inhibitor of nicotinamide adenine dinucleotide phosphate oxidase inhibited the hypoxia-increased D2 indicating a role for some reactive oxygen species in the mechanism of D2 increase. Further studies are required to clarify the precise molecular mechanisms involved in the D2 stabilization by hypoxia.
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PMID:Hypoxia stabilizes type 2 deiodinase activity in rat astrocytes. 1761 50

To improve prognosis in acute coronary syndrome, new clinical applications in terms of diagnosis, risk stratification, and treatment strategies are still under investigation. Ischemia-modified albumin was one of the novel markers of myocardial ischemia. In our study, we aimed to determine the prognostic significance of the albumin cobalt binding capacity test in patients with acute coronary syndromes. We compared the ischemia-modified albumin levels of patients with acute coronary syndrome with those of patients with stable coronary artery disease and those of normal individuals and found them to be significantly higher in the first group (P<0.05). A cutoff value of ischemia-modified albumin of 477 U/ml was found by using receiver operating characteristic curve analysis. Mortality in groups of patients whose ischemia-modified albumin levels were above 477 U (50%) was found to be significantly higher than in those whose levels were below 477 U (8.3%) (P<0.05). The sensitivity and specificity of the cutoff value, 477 U/ml, for the 1-year mortality were found to be 70 and 82%, respectively. Using the Cox regression model the relation of albumin cobalt binding capacity test results with mortality was statistically significant (beta=1.013, confidence interval 95%, P=0.01) and independent of the existence of hypertension, diabetes, and advanced age. In conclusion, ischemia-modified albumin was found to be significantly related to 1-year mortality. Prognostic significance of ischemia-modified albumin should be evaluated in large populated and randomized study groups. Afterwards, ischemia-modified albumin could be used in risk stratification modality in patients with acute coronary syndrome.
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PMID:Prognostic significance of ischemia-modified albumin in patients with acute coronary syndrome. 1762 86

Ischemia -modified albumin was regarded as an early marker of cardiac ischemia. On the other hand, it has been reported that increased ischemia-modified albumin levels are associated with unstable plaque processes like percutaneous coronary intervention, acute coronary syndrome or myocardial infarction. This prospective study aimed to investigate the role of ischemia-modified albumin in patients with peripheral vascular disease undergoing peripheral vascular intervention, a plaque-altering procedure without evidence of tissue ischemia. Peripheral vascular intervention was performed in 21 consecutive patients (68.2+/-13.3 years) with typical leg claudication and documented peripheral vascular disease. Additionally, 96 consecutive patients (66+/-12.0 years) undergoing routine exercise stress test for the exclusion of functionally relevant coronary artery disease were defined as controls. It was assumed that in the latter patients no unstable plaque-altering processes were present. Blood samples were drawn before, and 30 min and 3 h after, revascularization in the peripheral vascular intervention group, as well as before, and 30 min and 3 h after, maximum stress testing in the control group, respectively. Ischemia-modified albumin levels were analyzed using the albumin cobalt-binding test. In patients undergoing peripheral vascular intervention, ischemia-modified albumin increased from 116.6+/-19.1 U/ml at baseline to 132.0+/-19.3 U/ml 30 min after intervention (+14.4+/-15.7%, P<0.001) and decreased to 123.5+/-17.8 U/ml 3 h later (-5.7+/-10.5%, P<0.001 compared with postintervention, P<0.001 compared with baseline). The control group showed a slight but significant decrease in ischemia-modified albumin from 103.0+/-11.0 to 100.2+/-11.6 U/ml poststress (-2.2+/-11.5%, P<0.05) and returned close to baseline 3 h later (101.8+/-10.3 U/ml, +2.4+/-10.9%, P=NS, compared with poststress and with baseline). For both groups, ischemia-modified albumin showed no correlation with albumin (at baseline P=0.62) and total protein (P=0.67), but significant correlation with creatinine (P=0.04) and C-reactive protein (P=0.02). In addition, ischemia-modified albumin was independent of age, sex, alanine aminotransferase, aspartate aminotransferase, creatine kinase, creatine kinase-MB, cholesterol, and triglycerides. This study showed an increased basal ischemia-modified albumin level in patients with peripheral vascular disease undergoing peripheral vascular intervention. Ischemia-modified albumin levels transiently increased shortly after peripheral vascular intervention, indicating a strong correlation between serum concentration of ischemia-modified albumin and processes associated with acute plaque disruption/rupture.
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PMID:Effects of peripheral vascular intervention on ischemia-modified albumin. 1762 87

Transient reduction in coronary perfusion pressure in the isolated mouse heart increases microvascular resistance (paradoxical vasoconstriction) by an endothelium-mediated mechanism. To assess the presence and extent of paradoxical vasoconstriction in hearts from normal and diabetic rats and to determine whether increased heme oxygenase (HO)-1 expression and HO activity, using cobalt protoporphyrin (CoPP), attenuates coronary microvascular response, male Wistar rats were rendered diabetic with nicotinamide/streptozotocin for 2 wk and either CoPP or vehicle was administered by intraperitoneal injection weekly for 3 wk (0.5 mg/100 g body wt). The isolated beating nonworking heart was submitted to transient low perfusion pressure (20 mmHg), and coronary resistance (CR) was measured. During low perfusion pressure, CR increased and was associated with increased lactate release. In diabetic rats, CR was higher, HO-1 expression and endothelial nitric oxide synthase were downregulated, and inducible nitric oxide synthase and O(2)(-) were upregulated. After 3 wk of CoPP treatment, HO activity was significantly increased in the heart. Upregulation of HO-1 expression and HO activity by CoPP resulted in the abolition of paradoxical vasoconstriction and a reduction in oxidative ischemic damage. In addition, there was a marked increase in serum adiponectin. Elevated HO-1 expression was associated with increased expression of cardiac endothelial nitric oxide synthase, B-cell leukemia/lymphoma extra long, and phospho activator protein kinase levels and decreased levels of inducible nitric oxide synthase and malondialdehyde. These results suggest a critical role for HO-1 in microvascular tone control and myocardial protection during ischemia in both normal and mildly diabetic rats through the modulation of constitutive and inducible nitric oxide synthase expression and activity, and an increase in serum adiponectin.
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PMID:Beneficial effect of heme oxygenase-1 expression on myocardial ischemia-reperfusion involves an increase in adiponectin in mildly diabetic rats. 1790 3

Currently, the rapid diagnosis of mesenteric ischemia is problematic because of the nonspecificity of most laboratory assays and the unreliability of physical examinations. The evaluation of the cobalt-albumin binding assay (CABA) as a diagnostic marker for short-term risk stratification of emergency department patients presenting with symptoms of intestinal ischemia is reported. This preliminary study includes patients scheduled for exploratory laparotomy with symptoms of ischemic bowel and/or bowel obstruction. Approximately 10 mL of blood was drawn from each patient 1 hour preoperatively into a serum separator gel tube. After 30 minutes of clotting time, serum was collected and frozen at -80 degrees C. The CABA test was performed on the samples by an investigator blinded to the patient's condition, and values were compared with the clinical and pathologic diagnosis of ischemic bowel postoperatively. CABA test values are reported as absorbance units (ABSU) at 470 nm. Of the 26 patients enrolled in the study, 12 were clinically diagnosed with intestinal ischemia. These patients had significantly higher CABA test values (0.52 ABSU +/- 0.04 SEM) than patients without intestinal ischemia (0.31 ABSU +/- 0.02 SEM, p = 0.00023). Only two false-positives and no false-negatives were recorded. This resulted in a sensitivity of 100% and a specificity of 85.7% for the CABA test for these particular samples. The CABA test could be a useful tool for clinicians in the risk stratification of intestinal ischemia.
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PMID:Clinical utility of the cobalt-albumin binding assay in the diagnosis of intestinal ischemia. 1818 97

Diagnosis of cardiac ischemia in patients coming to emergency departments (ED) with symptoms of acute chest pain is often difficult. Many markers are sensitive and specific for the detection of myocardial necrosis but may not rise during reversible myocardial ischemia. Ischemia-modified albumin (IMA) has recently been shown to be a sensitive and early biochemical marker of ischemia. The variation laws were observed by measuring IMA and C-reactive protein (CRP) of 113 patients in ED within 12 hr after onset of chest pain. In the observation, blood was taken for IMA and CRP. Patients underwent standardized triage, diagnostic procedures, and treatment. Results of IMA and CRP were correlated with final diagnoses of nonischemic chest pain (NICP) and acute coronary syndrome (ACS). There were obvious distinction of IMA and CRP levels between the NICP and ACS groups. Receiver operator characteristic (ROC) curve analysis was used to determine the optimal cutoff of this assay for identifying individuals with ACS patients from NICP. The area under the curves of IMA is 0.948. The sensitivity and specificity of albumin cobalt binding (ACB) at a cutoff value of 70.0 units/mL were 94.4% and 82.6%, respectively. The area under the curves of CRP is 0.746. Sensitivity and specificity of CRP at a cutoff value of 3.16 mg/L were 70.0% and 73.9%, respectively. Negative predictive value (NPV) of IMA and CRP for ischemia origin was 79.2% and 38.6%, respectively. IMA may make an early diagnosis of acute coronary ischemia, and will improve the early diagnostic sensitivity and specificity of ACS.
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PMID:Assay of ischemia-modified albumin and C-reactive protein for early diagnosis of acute coronary syndromes. 1820 May 82


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