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)

We tested the hypothesis that phosphatidylinositol 3-kinase (PI 3-kinase)-dependent activation of Akt is essential for the expression of cardiac heat-shock protein 72 (HSP72) and that this pathway is impaired in the streptozotocin (STZ)-induced diabetic heart. STZ-induced male diabetic rats were treated with insulin (STZ-insulin group, n = 26) or vehicle (STZ-vehicle group, n = 61) for 3 weeks. Whole-body hyperthermia (43 degrees C for 20 min) was applied, and the heart was isolated 24 h later. Compared with control heart, hyperthermia-induced HSP72 expression and phosphorylation of Akt were attenuated in the STZ-vehicle heart. Pretreatment with wortmannin attenuated hyperthermia-induced HSP72 expression and phosphorylation of Akt. In isolated perfused heart experiments, the hyperthermia-treated STZ-vehicle heart showed poor left ventricular functional recovery during reperfusion after no-flow global ischemia compared with hyperthermia-treated control heart. Insulin treatment restored HSP72 expression and reperfusion-induced functional recovery. In cultured neonatal rat cardiomyocytes, hyperthermia-induced HSP72 expression was enhanced by insulin, together with tolerance against hypoxia-reoxygenation injury. Wortmannin and LY294002 inhibited hyperthermia-induced HSP72 expression and phosphorylation of Akt. Our results indicate that activation of Akt, in a PI 3-kinase-dependent manner, is essential for hyperthermia-induced HSP72 expression in association with cardioprotection, suggesting impairment of this signaling pathway in the STZ-induced diabetic heart, probably due to insulin deficiency.
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PMID:Phosphatidylinositol 3-kinase-dependent activation of akt, an essential signal for hyperthermia-induced heat-shock protein 72, is attenuated in streptozotocin-induced diabetic heart. 1664 87

We examined the effects of cyclosporin A (CsA), a drug that inhibits mitochondrial permeability transition pore, and insulin on ischemic spinal cord damage in rabbits. We assigned rabbits to 5 groups (n = 6 in each); sham barrier-opened group (sham BO), barrier-opened group (BO), barrier-opened-CsA group (BO-CsA), barrier-opened-insulin group (BO-I), and barrier-opened-CsA-insulin group (BO-CsA-I). The blood-spinal cord barrier was opened to facilitate drug penetration by a mild injury to the lumber spinal cord on day 1. CsA (10 mg/kg per day IV) was administered on day 3 to day 5 (total 30 mg/kg). Insulin was administered 30 min before ischemia. In all groups, spinal cord ischemia was produced on day 5 by occluding the abdominal aorta for 13 min. Neurological and histopathological evaluations were performed 4 days after ischemia. In group BO-CsA, blood glucose concentrations were significantly larger compared with the other four groups, and no protection was observed. In contrast, hindlimb motor function in groups BO-I and Bo-CsA-I and histopathology in group BO-CsA-I were significantly better than in groups sham BO, BO, and BO-CsA. The results indicate that insulin protects against ischemic spinal cord injury, whereas the effect of CsA is, at best, minimal.
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PMID:The effects of cyclosporin A and insulin on ischemic spinal cord injury in rabbits. 1671 16

Insulin induces the expression of the 70-kDa heat shock protein (Hsp70) in rat hearts. In this study, we examined insulin- and heat shock-treated hearts for improved contractile recovery after 30 min of ischemia, activation of the heat shock transcription factor, and localization of the Hsp70 in relation to dystrophin and alpha-tubulin. Adult male Sprague-Dawley rats were assigned to groups: 1) control, 2) sham control, 3) insulin injected (200 microU/g body wt), 4) heat shock treated (core body temperature 42 degrees C for 15 min), and 5) heat shock and insulin treated. Six hours later, hearts were isolated for Langendorff perfusion to determine cardiac function, or myocardial tissues were collected and prepared for either electrophoretic mobility shift assay, Western blot analysis, or immunofluorescence microscopy. Insulin treatment with 6 h of recovery enhances postischemic myocardial recovery of contractile function and increases Hsp70 expression through activation of the heat shock transcription factor. Insulin-treated hearts had elevated levels of Hsp70, particularly in the membrane fraction. In contrast, heat-shocked hearts had elevated levels of Hsp70 in the cytosol, membrane, and pellet fractions. After insulin treatment, Hsp70 was mostly colocalized to the plasma membrane with dystrophin. In contrast, after heat shock, Hsp70 was localized mostly between cardiomyocytes in apparent vascular or perivascular elements. The localization of Hsp70 is dependent on the inducing stimuli of either heat shock or insulin treatment. The cell membrane versus vascular localization of Hsp70 suggests the interesting possibility of functionally distinct roles for Hsp70 in the heart, whether induced by insulin or heat shock treatment.
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PMID:Insulin induces myocardial protection and Hsp70 localization to plasma membranes in rat hearts. 1673 49

We previously demonstrated that insulin has a neuroprotective role against oxidative stress, a deleterious condition associated with diabetes, ischemia, and age-related neurodegenerative diseases. In this study, we investigated the effect of insulin on neuronal glucose uptake and metabolism after oxidative stress in rat primary cortical neurons. On oxidative stress, insulin stimulates neuronal glucose uptake and subsequent metabolism into pyruvate, restoring intracellular ATP and phosphocreatine. Insulin also increases intracellular and decreases extracellular adenosine, counteracting the effect of oxidative stress. Insulin effects are apparently mediated by phosphatidylinositol 3-K and extracellular signal-regulated kinase signaling pathways. Extracellular adenosine under oxidative stress is largely inhibited after blockade of ecto-5'-nucleotidase, suggesting that extracellular adenosine results preferentially from ATP release and catabolism. Moreover, insulin appears to interfere with the ATP release induced by oxidative stress, regulating extracellular adenosine levels. In conclusion, insulin neuroprotection against oxidative stress-mediated damage involves 1) stimulation of glucose uptake and metabolism, increasing energy levels and intracellular adenosine and, ultimately, uric acid formation and 2) a decrease in extracellular adenosine, which may reduce the facilitatory activity of adenosine receptors.
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PMID:Insulin restores metabolic function in cultured cortical neurons subjected to oxidative stress. 1700 54

Insulin resistance (IR) precedes the onset of Type 2 diabetes, but its impact on preconditioning against myocardial ischemia-reperfusion injury is unexplored. We examined the effects of diazoxide and ischemic preconditioning (IPC; 5-min ischemia and 5-min reperfusion) on ischemia (30 min)-reperfusion (240 min) injury in young IR Zucker obese (ZO) and lean (ZL) rats. ZO hearts developed larger infarcts than ZL hearts (infarct size: 57.3 +/- 3% in ZO vs. 39.2 +/- 3.2% in ZL; P < 0.05) and also failed to respond to cardioprotection by IPC or diazoxide (47.2 +/- 4.3% and 52.5 +/- 5.8%, respectively; P = not significant). In contrast, IPC and diazoxide treatment reduced the infarct size in ZL hearts (12.7 +/- 2% and 16.3 +/- 6.7%, respectively; P < 0.05). The mitochondrial ATP-activated potassium channel (K(ATP)) antagonist 5-hydroxydecanoic acid inhibited IPC and diazoxide-induced preconditioning in ZL hearts, whereas it had no effect on ZO hearts. Diazoxide elicited reduced depolarization of isolated mitochondria from ZO hearts compared with ZL (73 +/- 9% in ZL vs. 39 +/- 9% in ZO; P < 0.05). Diazoxide also failed to enhance superoxide generation in isolated mitochondria from ZO compared with ZL hearts. Electron micrographs of ZO hearts revealed a decreased number of mitochondria accompanied by swelling, disorganized cristae, and vacuolation. Immunoblots of mitochondrial protein showed a modest increase in manganese superoxide dismutase in ZO hearts. Thus obesity accompanied by IR is associated with the inability to precondition against ischemic cardiac injury, which is mediated by enhanced mitochondrial oxidative stress and impaired activation of mitochondrial K(ATP).
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PMID:Myocardial preconditioning against ischemia-reperfusion injury is abolished in Zucker obese rats with insulin resistance. 1700 56

The presence of insulin receptor in the hippocampus suggests that this organ is a target for insulin. However, unlike the classic peripheral insulin target tissues such as adipocyte, muscle and liver, where the primary function of insulin is to regulate glucose homeostasis, insulin in the central nervous system (CNS) exhibits more diverse actions, most of which have not been clearly understood. A direct role of hippocampal insulin receptor signaling in improving cognitive functions, including learning and memory, and the association of insulin receptor deterioration with brain degenerative dementia (e.g., Alzheimer's disease) have attracted increasing interest. Additionally it has been shown that insulin can be a neuroprotective agent against memory loss induced by ischemia, lesions and some pharmacological agents. In the present study we evaluate the hypothesis that the bilateral intra CA1 insulin injection can protects against stress-induced memory deficit. Chronic restraint stress (2h per day x 7 days) significantly impaired spatial performance in Morris water maze and elevated serum corticosterone level. Intrahippocampal insulin microinjection was done 15-20 min before every stress episode. Insulin in low dose (0.5 MU) had no significant effect on memory deficit induced by stress. But in higher doses (6 and 12 MU) insulin protects animals against the deleterious effect of stress. Insulin alone daily injection had no effect on water maze performance. These results suggest that spatial learning and memory is compromised during chronic stress and insulin may protect against this effect.
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PMID:Insulin protects against stress-induced impairments in water maze performance. 1711 37

After the discovery that glycogen synthase kinase (GSK) 3beta plays a fundamental role in the regulation of the activity of nuclear factor kappaB, a number of studies have investigated the effects of this protein kinase in the regulation of the inflammatory process. The GSK-3beta inhibition, using genetically modified cells and chemically different pharmacological inhibitors, affects the regulation of various inflammatory mediators in vitro and in vivo. Insulin, an endogenous inhibitor of GSK-3 in the pathway leading to the regulation of glycogen synthase activity, has recently been clinically used in the therapy for septic shock. The beneficial anti-inflammatory effects of insulin in preclinical and clinical studies could possibly be due, at least in part, to the inhibition of GSK-3 and not directly correlated to the regulation of blood glucose. We describe the latest studies describing the effects of GSK-3 inhibition as potential target of the therapy for diseases associated with inflammation, ischemia/reperfusion, and shock.
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PMID:Glycogen synthase kinase 3beta as a target for the therapy of shock and inflammation. 1722 84

Insulin-like growth factor-1 (IGF-1) is essential to hippocampal neurogenesis and the neuronal response to hypoxia/ischemia injury. IGF (IGF-1 and -2) signaling is mediated primarily by the type 1 IGF receptor (IGF-1R) and modulated by six high-affinity binding proteins (IGFBP) and the type 2 IGF receptor (IGF-2R), collectively termed IGF system proteins. Defining the precise cells that express each is essential to understanding their roles. With the exception of IGFBP-1, we found that mouse hippocampus expresses mRNA for each of these proteins during the first 2 weeks of postnatal life. Compared to postnatal day 14 (P14), mRNA abundance at P5 was higher for IGF-1, IGFBP-2, -3, and -5 (by 71%, 108%, 100%, and 98%, respectively), lower for IGF-2, IGF-2R, and IGFBP-6 (by 65%, 78%, and 44%, respectively), and unchanged for IGF-1R and IGFBP-4. Using laser capture microdissection (LCM), we found that granule neurons and pyramidal neurons exhibited identical patterns of expression of IGF-1, IGF-1R, IGF-2R, IGFBP-2, and -4, but did not express other IGF system genes. We then compared IGF system expression in mature granule neurons and their progenitors. Progenitors exhibited higher mRNA levels of IGF-1 and IGF-1R (by 130% and 86%, respectively), lower levels of IGF-2R (by 72%), and similar levels of IGFBP-4. Our data support a role for IGF in hippocampal neurogenesis and provide evidence that IGF actions are regulated within a defined in vivo milieu.
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PMID:Expression of insulin-like growth factor system genes during the early postnatal neurogenesis in the mouse hippocampus. 1745 96

Heart disease is the leading cause of death in patients with insulin resistance and type 2 diabetes (DM2). Even in the absence of coronary artery disease and hypertension, functional and structural abnormalities exist in patients with well-controlled and uncomplicated DM2. These derangements are collectively designated by the term diabetic cardiomyopathy (DCM). Changes in myocardial energy metabolism, due to altered substrate supply and utilization, largely underlie the development of DCM. Insulin is an important regulator of myocardial substrate metabolism, but also exerts regulatory effects on intracellular Ca2+ handling and cell survival. The current paper reviews the multiple functional and molecular effects of insulin on the heart, all of which ultimately seem to be cardioprotective both under normal conditions and under ischemia. In particular, the dismal consequences of myocardial insulin resistance contributing to the development of DCM will be discussed.
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PMID:Myocardial insulin action and the contribution of insulin resistance to the pathogenesis of diabetic cardiomyopathy. 1755 6

Six hours after insulin treatment, hearts express heat shock protein 70 (Hsp70) and have improved contractile function after ischemia-reperfusion injury. In this study we examined hearts 1 h after insulin treatment for contractile function and for expression of Hsp70 and Hsp27. Adult, male Sprague-Dawley rats were assigned to groups: 1) sham, 2) control, 3) insulin injected (200 microU/g body wt), 4) heat shock treated (core body temperature, 42 degrees C for 15 min), and 5) heat shock and insulin treated. At 1 h after these treatments, hearts were isolated, equilibrated to Langendorff perfusion for 30 min, and then subjected for 30 min no-flow global ischemia (37 degrees C) followed by 2 h of reperfusion. Insulin-treated hearts had significantly increased contractile function compared with control hearts. At 1 h after insulin treatment, a minimal change in Hsp70 and Hsp27 content were detected. By 3 h after insulin treatment, a significant increase in Hsp70, but not Hsp27, was detected by Western blot analysis. By immunofluorescence, minimal Hsp70 was detected in insulin-treated hearts, whereas Hsp27 was detected in all hearts, indicative of its constitutive expression. Phosphospecific isoforms of Hsp27 were detected in insulin-, heat shock-, and heat shock and insulin-treated hearts. After ischemia and reperfusion, the insulin-treated hearts had significantly elevated levels of phosphorylated Hsp27. Inhibition of p38 MAPK with SB-203580 blocked the insulin-induced phosphorylation of Hsp27 and the improved functional recovery. In conclusion, insulin induces an apparent rapid phosphorylation of Hsp27 that is associated with improved functional recovery after ischemia-reperfusion injury.
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PMID:Insulin-induced myocardial protection in isolated ischemic rat hearts requires p38 MAPK phosphorylation of Hsp27. 1790 11


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