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)

Activated protein C (APC) is a serine protease with anticoagulant and direct cytoprotective activities. Early postischemic APC application activates the cellular protein C pathway in brain endothelium and neurons, which is neuroprotective. Whether late APC administration after a transient ischemic attack is neuroprotective and whether APC influences brain repair is not known. Here, we determined safety and efficacy of late APC and tissue-plasminogen activator (tPA) administrations in a mouse model of transient brain ischemia. tPA given at 6 h after onset of ischemia killed all mice within 2 d, whereas APC given at 6 or 24 h after ischemia onset improved significantly functional outcome and reduced spread of the ischemic lesion. At 7 d postischemia, APC multiple dosing (0.8 mg/kg, i.p.) at 6-72 or 72-144 h enhanced comparably cerebral perfusion in the ischemic border by approximately 40% as shown by in vivo lectin-FITC angiography, blocked blood-brain barrier leakage of serum proteins, and increased the number of endothelial replicating cells by 4.5- to 4.7-fold. APC multidosing at 6-72 h or 72-144 h increased proliferation of neuronal progenitor cells in the subventricular zone (SVZ) by 40-50% and migration of newly formed neuroblasts from the SVZ toward the ischemic border by approximately twofold. The effects of APC on neovascularization and neurogenesis were mediated by protease-activated receptor 1 and were independent of the reduction by APC of infarction volume. Our data show that delayed APC administration is neuroprotective and mediates brain repair (i.e., neovascularization and neurogenesis), suggesting a significant extension of the therapeutic window for APC intervention in postischemic brain.
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PMID:Activated protein C promotes neovascularization and neurogenesis in postischemic brain via protease-activated receptor 1. 1903 71

Three major cytokines, namely, tumor necrosis factor (TNF-alpha), interleukin (IL)-1, and IL-6 are produced by cultured brain cells after various stimuli such as ischemia. Neurones, astrocytes, microglia and oligodendrocytes can produce inflammatory mediators, and cytokine receptors are expressed constitutionally throughout the Central Nervous System (CNS), albeit at low levels. Cytokines are involved in virtually every facet of stroke and they have numerous pro-inflammatory and pro-coagulant effects on endothelium. TNF-alpha expression after stroke stimulates expression of tissue factor and adhesion molecules for leukocytes, release of interleukin-1 (IL-1), nitric oxide, factor VIII/von Willebrand factor, platelet-activating factor and endothelin, suppression of the thrombomodulin-protein C-protein S system, reduction of tissue-plasminogen activator and release of plasminogen activator inhibitor-1. Research into the actions of IL-1beta in the brain initially focused on its role in host defence responses to systemic disease. IL-1beta can also elicit an array of responses which could either inhibit, exacerbate or induce neuronal damage and death. IL-6 can be induced by a variety of molecules including IL-1, TNF-alpha, transforming growth factor-beta and prostaglandins (PGs), and many other mediators such as b-amyloid, interferon-g (IFNg) and IL-4 can potentiate these primary inducers, highlighting the complex nature of IL-6 modulation. Several studies reported that plasma levels of TNF-alpha and IL-6 are associated with prognosis after ischemic stroke and our group showed that plasma levels of cytokines such as TNF-alpha, IL-1beta are different in every diagnostic subtype of ischemic stroke, and how plasma levels of some immunoinflammatory markers and thrombotic-phybrinolitic markers are predictive of acute ischemic stroke diagnosis in the acute setting.
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PMID:Inflammatory cytokines in acute ischemic stroke. 1907 34

Altered coagulation and inflammation contribute to the pathogenesis of ischemic renal injury. Thrombomodulin is a necessary factor in the anticoagulant protein C pathway and has inherent anti-inflammatory properties. We studied the effect of soluble thrombomodulin (sTM) in a hypoperfusion model of ischemic kidney injury. To markedly reduce infrarenal aortic blood flow and femoral arterial pressures, we clamped the suprarenal aorta of rats, occluding them 90%, for 60 min. Reversible acute kidney injury (AKI) occurred at 24 h in rats subjected to hypoperfusion. Histologic analysis at 24 h revealed acute tubular necrosis (ATN), and intravital two-photon microscopy showed flow abnormalities in the microvasculature and defects of endothelial permeability. Pretreatment with rat sTM markedly reduced both I-R-induced renal dysfunction and tubular histologic injury scores. sTM also significantly improved microvascular erythrocyte flow rates, reduced microvascular endothelial leukocyte rolling and attachment, and minimized endothelial permeability to infused fluorescence dextrans, assessed by intravital quantitative multiphoton microscopy. Furthermore, sTM administered 2 h after reperfusion protected against ischemia-induced renal dysfunction at 24 h and improved survival. By using an sTM variant, we also determined that the protective effects of sTM were independent of its ability to generate activated protein C. These data suggest that sTM may have therapeutic potential for ischemic AKI.
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PMID:Soluble thrombomodulin protects ischemic kidneys. 1917 99

Thrombomodulin (TM), a cell surface-expressed glycoprotein predominantly synthesized by vascular endothelial cells, is a critical cofactor for thrombin-medicated activation of protein C. TM thus has an impact on coagulation, inflammation, and fibrinolysis. In this study, we investigated expression of endothelial TM in the dorsal skin of the rat as an ischemic flap model. Twenty male Wistar rats weighing between 250 and 350 g were used in the study. Nine by 3-cm, full-thickness, caudally based random pattern dorsal skin flaps were elevated. The rats were randomized into 2 subgroups according to the evaluation time. Tissue blood flow of the skin flaps was measured 4 times (before the operation and on days 1, 3, and 7) at 1, 3, and 5 cm distal to the baseline of the skin flap. Skin flap samples including subcutaneous tissue were taken from killed rats at day 3 (n = 10) and 7 (n = 10) for histologic assessment. These samples were also taken from the midline at 1, 3, and 5 cm distal to the baseline of the skin flaps. The survival rate of the skin flaps was measured on day 7. According to the blood flow rate change, we found that there were significant differences between the 1-, 3-, and 5-cm samples throughout the experiment. The most profound change was that it was at 5 cm in which there was an initial pattern of reduced perfusion followed by cessation of perfusion. On the third day, positive immunoperoxidase staining specific for TM was detected in all the specimens of the skin biopsies taken from 1 and 3 cm. The 5-cm samples demonstrated very little evidence of necrosis and had negative immunoperoxidase staining for TM. The 1-cm samples were found to have preserved morphologic features present on days 3 and 7. The 3-cm samples showed no evidence of necrosis, though some of the capillary vessels were filled with aggregated blood cells. The vascular wall had negative peroxidase staining for endothelial TM. At 5 cm, there was clear evidence of necrosis, some found within the capillary vessels, which were filled with aggregated blood cells. These samples also had negative peroxidase staining for TM. On day 7, the survival rate of skin flaps was 45.35%. In this study, we demonstrate that tissue ischemia is an important factor, particularly in down-regulating TM transcription. TM depletion from the vascular cells and microthrombus formation occurred in the ischemic areas, playing an important role in secondary aggravation of tissue ischemia.
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PMID:Expression of the endothelial thrombomodulin (TM) on the ischemic rat flap model: preliminary study. 1946 Dec 88

Hepatic ischemia and reperfusion (IR) injury is a major clinical problem often leading to acute kidney injury characterized by early endothelial cell apoptosis, subsequent neutrophil infiltration, proximal tubule necrosis/inflammation, impaired vascular permeability, and disintegration of the proximal tubule filamentous actin cytoskeleton. Activated protein C is a major physiological anticoagulant with anti-inflammatory and anti-apoptotic activities in endothelial cells. Here we tested if activated protein C would attenuate hepatic and renal injury caused by hepatic ischemia and reperfusion. Both liver and kidney injury were significantly reduced when activated protein C was given immediately before and 2 h after liver reperfusion, in that there was reduced renal endothelial and hepatocyte apoptosis, as well as reduced hepatic and renal tubular necrosis. Further, the administration of activated protein C also reduced the expression of several pro-inflammatory genes, liver and kidney filamentous-actin degradation, and neutrophil infiltration, and resulted in better preservation of vascular permeability of both the liver and kidney than is normally seen after liver ischemia and reperfusion. These protective effects of activated protein C were due to protease-activated receptor-1 modulation since administration of a selective receptor antagonist dose-dependently inhibited its ameliorative effects in both organs after liver ischemia and reperfusion. Our results suggest the powerful multi-organ protective effects of activated protein C may improve outcome in those patients at significant risk of developing acute kidney injury following liver ischemia and reperfusion during transplantation.
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PMID:Human activated protein C attenuates both hepatic and renal injury caused by hepatic ischemia and reperfusion injury in mice. 1962 89

Sepsis associated Acute Kidney Injury (SA-AKI) is the leading cause of AKI in the hospital setting and its incidence is increasing. Although the exact pathophysiology and phenotype of SA-AKI are not known, it is widely accepted that SA-AKI has a multi-injury pathway. This form of AKI has components of ischemia-reperfusion injury, direct inflammatory injury, coagulation and endothelial cell dysfunction, and apoptosis. As such, multiple agents have been shown in pre-clinical studies to ameliorate SA-AKI, but there are no interventions currently available for the treatment of SA-AKI. Promising agents that are in development include toll-like receptor inhibition, IL-10 augmentation, modulators of the protein C pathway, and mesenchymal stem cell mediated therapeutics. The aim of this review is to review the pathophysiology of SA-AKI and the therapeutic interventions that are under development to treat this complex and morbid disease.
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PMID:Novel therapeutic targets for prevention and therapy of sepsis associated acute kidney injury. 1971 36

Protein C is a plasma serine protease that when activated plays a central role in modulating the function of the vascular endothelium and its interface with the innate immune system. Activated protein C (APC) has a dual mechanism of action via the feedback inhibition of thrombin generation, and as an agonist of protease activated receptor-1 (PAR-1). Through different cofactor interactions, this dual mechanism of antithrombotic and cytoprotective activity results in the ability of APC to modulate endothelial dysfunction by blocking cytokine signaling, functional cell adhesion expression, vascular permeability, apoptosis, and modulating leukocyte migration and adhesion. Deficiency in protein C, which occurs during systemic inflammatory activation, is highly associated with organ dysfunction. APC has shown efficacy in a number of preclinical models of thrombosis and ischemia, and the recombinant human APC drotrecogin alfa (activated), reduces mortality in patients with high-risk severe sepsis. The ability of APC to suppress pro-inflammatory pathways and enhance cellular survival suggests that APC plays a key role in the adaptive response to protect the vessel wall from insult and to enhance endothelial, cellular, and organ survival. The focus of this review will be to summarize the emerging data suggesting the potential therapeutic benefit of APC and related members of the pathway in the prevention and treatment of acute kidney injury.
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PMID:Activated protein C and acute kidney injury: Selective targeting of PAR-1. 1971 37

Acute myocardial infarction (AMI) is a common cause of death for which effective treatments are available provided that diagnosis is rapid. The current diagnostic gold standards are circulating cardiac troponins I and T. However, their slow release delays diagnosis, and their persistence limits their utility in the identification of reinfarction. The aim was to identify candidate biomarkers of AMI. Isolated mouse hearts were perfused with oxygenated protein-free buffer, and coronary effluent was collected after ischemia or during matched normoxic perfusion. Effluents were analyzed using proteomics approaches based on one- or two-dimensional initial separation. Of the 459 proteins identified after ischemia with one-dimensional separation, 320 were not detected in the control coronary effluent. Among these were all classic existing biomarkers of AMI. We also identified the cardiac isoform of myosin-binding protein C in its full-length form and as a 40-kDa degradation product. This protein was not detected in the other murine organs examined, increased markedly with even trivial myocardial infarction, and could be detected in the plasma after myocardial infarction in vivo, a profile compatible with a biomarker of AMI. Two-dimensional fluorescence DIGE of ischemic and control coronary effluents identified more than 200 asymmetric spots verified by swapping dyes. Once again existing biomarkers of injury were confirmed as well as posttranslational modifications of antioxidant proteins such as peroxiredoxins. Perfusing hearts with protein-free buffers provides a platform of graded ischemic injury that allows detailed analysis of protein release and identification of candidate cardiac biomarkers like myosin-binding protein C.
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PMID:Identification of cardiac myosin-binding protein C as a candidate biomarker of myocardial infarction by proteomics analysis. 1972 Oct 77

Activated protein C (APC) is a vitamin-K dependent natural anticoagulant protein. With its function in blood clotting reaction, APC can reduce the risk of venous thrombosis to prevent ischemic disease. A number of in vivo and in vitro studies over the past few decades have revealed that APC also exerted cytoprotective effects to decrease the mortality caused by endotoxin, sepsis, and brain ischemic stroke. The direct cytoprotective role requires APC binding to the endothelial protein C receptor (EPCR) and activating protease activated receptor-1 (PAR-1). It is now believed that the beneficial characters of APC are partially independent from its anticoagulant activity, though more studies need to be done to demonstrate the exact molecular mechanism. In this review, we have linked the cytoprotective effects of APC including the anti-inflammatory and anti-apoptosis activities to myocardial ischemic injury caused by cardiac ischemia reperfusion. Specifically, we have tried to combine the potential signaling pathways initiated by APC with the well-known adaptive signaling such as AMP-activated protein kinase (AMPK), PI3K/Akt and ERK/MAPK pathways that contribute to the cardioprotection against myocardial ischemia injury. We speculate that APC protects against cardiac ischemia injury via triggering crucial cardioprotective signaling pathways, and these effects are mostly associated with its cytoprotective activity but independent on its anticoagulant activity.
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PMID:Activated protein C: a potential cardioprotective factor against ischemic injury during ischemia/reperfusion. 1995 50

Small-for-size liver grafts are a serious obstacle for partial orthotopic liver transplantation. Activated protein C (APC), a potent anticoagulant serine protease, is known to have cell-protective properties due to its anti-inflammatory and antiapoptotic activities. This study was designed to examine the cytoprotective effects of a preservation solution containing APC on small-for-size liver grafts, with special attention paid to ischemia-reperfusion injury and shear stress in rats. APC exerted cytoprotective effects, as evidenced by (1) increased 7-day graft survival; (2) decreased initial portal pressure and improved hepatic microcirculation; (3) decreased levels of aminotransferase and improved histological features of hepatic ischemia-reperfusion injury; (4) suppressed infiltration of neutrophils and monocytes/macrophages; (5) reduced hepatic expression of tumor necrosis factor alpha and interleukin 6; (6) decreased serum levels of hyaluronic acid, which indicated attenuation of sinusoidal endothelial cell injury; (7) increased hepatic levels of nitric oxide via up-regulated hepatic endothelial nitric oxide synthesis expression together with down-regulated hepatic inducible nitric oxide synthase expression; (8) decreased hepatic levels of endothelin 1; and (9) reduced hepatocellular apoptosis by down-regulated caspase-8 and caspase-3 activities. These results suggest that a preservation solution containing APC is a potential novel and safe product for small-for-size liver transplantation, alleviating graft injury via anti-inflammatory and antiapoptotic effects and vasorelaxing conditions.
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PMID:The cytoprotective effects of addition of activated protein C into preservation solution on small-for-size grafts in rats. 2003 25


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