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)

The tissue type plasminogen activator (t-PA) is a serine protease that is involved in neuronal plasticity and cell death induced by excitotoxins and ischemia in the brain. t-PA activity in the central nervous system is regulated through the activation of serine protease inhibitors (serpins) such as the plasminogen activator inhibitor (PAI-1), the protease nexin-1 (PN-1), and neuroserpin (NSP). Recently we demonstrated in vitro that PAI-1 produced by astrocytes mediates the neuroprotective effect of the transforming growth factor-beta1 (TGF-beta1) in NMDA-induced neuronal cell death. To investigate whether serpins may be involved in neuronal cell death after cerebral ischemia, we determined, by using semiquantitative RT-PCR and in situ hybridization, that focal cerebral ischemia in mice induced a dramatic overexpression of PAI-1 without any effect on PN-1, NSP, or t-PA. Then we showed that although the expression of PAI-1 is restricted to astrocytes, PN-1, NSP, and t-PA are expressed in both neurons and astrocytes. Moreover, by using semiquantitative RT-PCR and Western blotting, we observed that only the expression of PAI-1 was modulated by TGF-beta1 treatment via a TGF-beta-inducible element contained in the PAI-1 promoter (CAGA box). Finally, we compared the specificity of TGF-beta1 action with other members of the TGF-beta family by using luciferase reporter genes. These data show that TGF-beta and activin were able to induce the overexpression of PAI-1 in astrocytes, but that bone morphogenetic proteins, glial cell line-derived neutrophic factor, and neurturin did not. These results provide new insights into the regulation of the serpins/t-PA axis and the mechanism by which TGF-beta may be neuroprotective.
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PMID:Transforming growth factor-beta1 as a regulator of the serpins/t-PA axis in cerebral ischemia. 1042 56

The mechanisms underlying cerebral microvascular perfusion deficit resulting from occlusion of the middle cerebral artery (MCA) require elucidation. We, therefore, tested the hypothesis that intravascular fibrin deposition in situ directly obstructs cerebral microcirculation and that local changes in type 1 plasminogen activator inhibitor (PAI-1) gene expression contribute to intravascular fibrin deposition after embolic MCA occlusion. Using laser-scanning confocal microscopy (LSCM) in combination with immunofluorescent staining, we simultaneously measured in three dimensions the distribution of microvascular plasma perfusion deficit and fibrin(ogen) immunoreactivity in a rat model of focal cerebral embolic ischemia (n = 12). In addition, using in situ hybridization and immunostaining, we analyzed expression of PAI-1 in ischemic brain (n = 13). A significant (p < 0.05) reduction of cerebral microvascular plasma perfusion accompanied a significant (p < 0.05) increase of intravascular and extravascular fibrin deposition in the ischemic lesion. Microvascular plasma perfusion deficit and fibrin deposition expanded concomitantly from the subcortex to the cortex during 1 and 4 hr of embolic MCA occlusion. Three-dimensional analysis revealed that intravascular fibrin deposition directly blocks microvascular plasma perfusion. Vascular plugs contained erythrocytes, polymorphonuclear leukocytes, and platelets enmeshed in fibrin. In situ hybridization demonstrated induction of PAI-1 mRNA in vascular endothelial cells in the ischemic region at 1 hr of ischemia. PAI-1 mRNA significantly increased at 4 hr of ischemia. Immunohistochemical staining showed the same pattern of increased PAI-1 antigen in the endothelial cells. These data demonstrate, for the first time, that progressive intravascular fibrin deposition directly blocks cerebral microvascular plasma perfusion in the ischemic region during acute focal cerebral embolic ischemia, and upregulation of the PAI-1 gene in the ischemic lesion may foster fibrin deposition through suppression of fibrinolysis.
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PMID:Cerebral microvascular obstruction by fibrin is associated with upregulation of PAI-1 acutely after onset of focal embolic ischemia in rats. 1059 71

To explore the relationship between disorders of endogenous fibrinolysis and thrombosis in patients with lower extremity ischemia, we measured the activity of tissue plasminogen activator (tPAac) and plasminogen activator inhibitor (PAlac) and the antigens of tissue plasminogen activator (tPAa) and inhibitor (PAla) in plasma from 420 patients treated for lower extremity ischemia. Values and ratios observed were compared with those in healthy volunteers. Additionally, values and ratios in the patients were examined with respect to the severity of ischemia and site of atherosclerotic occlusion or stenosis (pelvic compared with femoropopliteal or crural). Patients with lower extremity ischemia had higher plasma concentrations of PAla (p<0.01) and PAlac (p<0.0001) than healthy volunteers. In patients with rest pain or gangrene, the ratio of tPAac to PAlac was higher than in patients with claudication (p<0.05). The elevation of tPAac in patients with the more severe form of lower extremity ischemia is probably the feedback protective reaction on prothrombotic mechanisms of the organism suffered from severe atherosclerosis. Results did not vary according to the site of occlusion or stenosis. Our study found defects in endogenous fibrinolysis in patients with lower extremity ischemia. A defect in fibrinolysis may contribute to the development of thrombosis in native arteries and bypasses.
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PMID:Endogenous fibrinolysis in patients with lower extremity ischemia. 1094 87

Information is lacking regarding dynamic platelet accumulation at the site of the occluded middle cerebral artery (MCA) and the relationship between platelet aggregation in downstream cerebral microvessels and loss of perfusion and vascular integrity of these microvessels. In the present study, we employed a model of embolic MCA occlusion in the rat to simultaneously measure temporal and spatial profiles of platelet accumulation at the site of the embolus occluding the MCA and within downstream cerebral microvessels. We also measured the integrity of microvessels and matrix metalloproteinase (MMP) activity in ischemic brain. Rats (n=36) were subjected to embolic MCA occlusion. Immunohistochemistry was used to detect microvascular integrity, plasminogen activator inhibitor 1 (PAI-1) and the deposition of fibrin. SDS-PAGE zymography was used to measure MMP2 and MMP9 activities. Accumulation of platelets and increases in PAI-1 immunoreactivity at the site of the embolus occluding the MCA were detected 1 h (n=7) and 4 h (n=7) after ischemia, respectively, and numbers of GPIIb/IIIa immunoreactive downstream cerebral microvessels increased significantly (209+/-59; n=7; P<0.05) 4 h after ischemia, suggesting dynamic platelet aggregation. A significant (n=7; P<0.01) diffuse loss of type IV collagen immunoreactivity in microvessels was temporally associated with platelet GPIIb/IIIa immunoreactivity within the vessels. Triple immunostaining revealed that microvessels containing platelet aggregates exhibited loss of type IV collagen immunoreactivity and both intra- and extra-vascular fibrin deposition, suggesting that intravascular platelet aggregation is associated with decreases in the integrity of the microvascular basal lamina and blood-brain barrier leakage. A significant increase (P<0.05) in MMP9 was detected at 4 h (n=3) and 24 h (n=3) after ischemia but levels of MMP2 were not significantly changed in ischemic brain. Our data suggest that dynamic platelet aggregation in ischemic brain may contribute to time-dependent resistance to fibrinolysis. In addition, platelet deposition and increased MMP9 coincided with degradation of type IV collagen and loss of vascular integrity. These data suggest an important role for post-occlusive distal platelet deposition in the pathophysiology of stroke.
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PMID:Dynamic platelet accumulation at the site of the occluded middle cerebral artery and in downstream microvessels is associated with loss of microvascular integrity after embolic middle cerebral artery occlusion. 1153 35

Thrombotic microangiopathies (TMA) encompass various severe diseases characterized by microangiopathic hemolytic anemia and peripheral thrombocytopenia, associated with fever, neurological signs and renal involvement. Microvascular thrombosis is the typical lesion, and results in tissue ischemia. Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are the two most classical forms. These two entities are clinically and histopathologically closely related. There is a body of evidence suggesting that endothelial cell injury is the initial event in TTP and HUS, and that it may be related to a large number of triggering factors, such as infection, connective tissue disease, drugs, cancer and chemotherapy, transplantation, and pregnancy. Endothelial cell injury enhances the release of ultra large forms of von Willebrand factor (ULvWF) multimers and other prothrombotic agents, such as plasminogen activator inhibitor and platelet activating factor, whereas it decreases the release of prostaglandin-I2, a strong inhibitor of platelet aggregation. Recently however, it has been shown that TTP and HUS were pathophysiologically distinct. Actually, TTP is associated with a deficiency in von Willebrand factor-cleaving protease, an enzyme involved in cleavage of ULvWF into circulating 200 kDa and 350 kDa fragments. This deficiency may be either congenital or acquired, and then related to an IgG inhibitory autoantibody. This protease deficiency may account for the high amounts of plasmatic ULvWF in TTP patients. In HUS, vWF-cleaving protease activity is found normal. HUS encompasses two distinct entities. Epidemic, or diarrhea-associated HUS, is associated with verotoxin or Shiga toxin-associated enterobacteriaceae. These toxins are directly responsible for endothelial cell injury. Sporadic HUS (also termed atypical HUS in children) is closely related to TTP, and shares the same triggering factors. Familial HUS has been associated in some cases with hypocomplementemia and factor H dysfunction, the pathophysiological role of which remains unclear. The study of the different triggering factors and predisposing factors may be useful to define different subsets of TMA, that may be characterized by their course and prognosis.
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PMID:[Pathophysiology of thrombotic microangiopathies: current understanding]. 1221 98

AIMS: Nitric oxide (NO) has protective effects against ischemia-reperfusion (I/R) injury and plays an important role in ischemic preconditioning. Type 1 plasminogen activator inhibitor (PAI-1) regulates plasminogen activators, which may have cytotoxic effects in I/R injury. I/R injury is reduced by the inhibition of fibrinolytic enzymes. To clarify the mechanism of ischemic preconditioning, PAI-1 induction and NO generation were studied in hepatic ischemic preconditioning. METHODS: Total hepatic ischemia was achieved by Pringle's maneuver. FK409 was used as an NO donor. Plasma alanine aminotransferase (ALT) and hyaluronic acid (HA) were measured to estimate hepatic damage and serum nitrite (NO(2)(-)) and nitrate (NO(3)(-)) were also determined to assess NO generation. Reserve transcription-polymerase chain reaction (RT-PCR) and in situ hybridization were carried out to determine the quantitative changes in the expression of PAI-1 mRNA. Plasma PAI-1 concentration was determined using an enzyme-linked immunosorbent assay (ELISA) system. RESULTS: No increase in ALT or HA was found with 5 min I/R. NO and PAI-1 in plasma and PAI-1 mRNA in liver were not increased in the ischemic period, but were increased during the reperfusion period. Infusion of FK409 stimulated induction of PAI-1 mRNA dose dependently. In situ hybridization studies indicated that hepatocytes expressed PAI-1 mRNA after I/R treatment. CONCLUSIONS: I/R increased the concentration of plasma PAI-1. Reperfusion following ischemia was needed for the induction of PAI-1 mRNA and increase of plasma NO concentration. FK409 stimulated PAI-1 mRNA induction in the liver. These results indicate that PAI-1 is a component of the ischemic preconditioning mechanisms, which is stimulated by NO generation.
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PMID:Expression of type 1 plasminogen activator inhibitor and nitric oxide generation in ischemic preconditioning of rat liver. 1269 56

Necrosis and apoptosis are the two fundamental hallmarks of neuronal death in stroke. Nevertheless, thrombolysis, by means of the recombinant serine protease t-PA, remains until now the only approved treatment of stroke in man. Over the last years, the cytokine termed Transforming Growth Factor-beta 1 (TGF-beta 1) has been found to be strongly up regulated in the central nervous system following ischemia-induced brain damage. Recent studies have shown a neuroprotective activity of TGF-beta 1 against ischemia-induced neuronal death. In vitro, TGF-beta 1 protects neurons against excitotoxicity by inhibiting the t-PA-potentiated NMDA-induced neuronal death through a mechanism involving the up-regulation of the type-1 plasminogen activator inhibitor (PAI-1) in astrocytes. Altogether, these observations suggest that either TGF-beta signaling or TGF-beta 1-modulated genes could be good targets for the development of new therapeutic strategies for stroke in man.
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PMID:[Does transforming growth factor-beta (TGF-beta) act as a neuroprotective agent in cerebral ischemia?]. 1291 Jun 29

1. Necrosis and apoptosis are the two fundamental hallmarks of neuronal death in stroke. Nevertheless, thrombolysis, by using the recombinant serine protease t-PA, remains until now the only approved treatment of stroke in man. 2. Over the last years, the cytokine termed Transforming Growth Factor-beta1 (TGF-beta1) has been found to be strongly up-regulated in the central nervous system following ischemia-induced brain damage. 3. Recent studies have shown a neuroprotective activity of TGF-beta1 against ischemia-induced neuronal death. In vitro, TGF-beta1 protects neurons against excitotoxicity by inhibiting the t-PA-potentiated NMDA-induced neuronal death through a mechanism involving the up-regulation of the type-1 plasminogen activator inhibitor (PAI-1) in astrocytes 4. In addition, TGF-beta1 has been recently characterized as an antiapoptotic factor in a model of staurosporine-induced neuronal death through a mechanism involving activation of the extracellular signal-regulated kinase 1/2 (Erk1/2) and a concomitant increase phosphorylation of the antiapoptotic protein Bad. 5. Altogether, these observations suggest that either TGF-beta signaling or TGF-beta1-modulated genes could be good targets for the development of new therapeutic strategies for stroke in man.
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PMID:Transforming growth factor-beta and ischemic brain injury. 1451 14

Previous studies have shown that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) protect the brain against ischemic injury by upregulating endothelial nitric oxide synthase (eNOS). Here, we tested the hypothesis that statins provide additional beneficial effects by also upregulating endogenous tissue plasminogen activator (tPA) and enhancing clot lysis in a mouse model of embolic focal ischemia. Heterologous blood clots (0.2 mm) were injected into the distal internal carotid artery to occlude blood flow in the middle cerebral artery territory after long-term (14 days) simvastatin, atorvastatin or vehicle treatment. Ischemic lesion volume, neurologic deficits, as well as residual blood clots were measured at 22 h. Reverse transcription-polymerase chain reaction assessed mRNA levels of eNOS, tPA, and the endogenous plasminogen activator inhibitor PAI-1. Ischemic lesion volumes and neurologic deficits were significantly reduced in wild-type mice by both simvastatin and atorvastatin. Statins increased eNOS and tPA mRNA levels but did not change mRNA levels of PAI-1. In eNOS knockout mice, atorvastatin reduced the volume of ischemic tissue and improved neurologic outcomes after arterial occlusion by blood clot emboli. In contrast, statins did not have protective effects in tPA knockout mice after embolic focal ischemia, but only in a filament model where focal ischemia was achieved via mechanical occlusion. These results suggest that statins protect against stroke by multiple mechanisms involving both eNOS and tPA. The involvement of each pathway may be revealed depending on the choice of experimental stroke model.
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PMID:Protective effects of statins involving both eNOS and tPA in focal cerebral ischemia. 1571 55

Peritoneum has an intrinsic fibrinolytic activity that breaks the peritoneal adhesions. Peritoneal injuries with ischemia interfere this fibrinolytic activity and cause adhesions. Pentoxifylline, a methyl xanthine derivative, improves blood flow by decreasing its viscosity and also increases fibrinolytic activity in plasma. We hypothesized that pentoxifylline would increase peritoneal fibrinolysis and ameliorate adhesions. A rat model of peritoneal adhesion (cecal abrasion with gauze, n = 15 for each group) was used to test this hypothesis and cardinal parameters of peritoneal fibrinolysis were measured in peritoneal samples. No medication was given in control animals, while pentoxifylline was administered intraperitonealy (IP) (25 mg/kg, before abdominal closure to whole abdomen) or intravenously (IV) (25 mg/kg, for 9 days after operation) in the experimental groups. At postoperative day 10, peritoneal biopsies were obtained and adhesions were graded qualitatively. Activities and concentrations of tissue plasminogen activator (tPA), plasminogen activator inhibitor type 1 (PAI-1), tPA/PAI-1 complex and hydroxyproline contents were determined. Total adhesion scores were decreased in both treated groups. Mean levels of tPA concentration and tPA activity were increased in the treated groups compared to controls (p < 0.001 and p = 0.001, respectively). The tPA/PAI-1 complex levels were similar among the three groups. PAI-1 levels were lower in animals receiving IP pentoxifylline compared to control animals and those treated with IV pentoxifylline (p = 0.048, p = 0.015, respectively). Peritoneal hydroxyproline levels were similar among the three groups. Our results suggest that pentoxifylline administration either through IV or IP may reduce peritoneal adhesion formation probably by altering peritoneal fibrinolytic activity.
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PMID:Pentoxifylline, a methyl xanthine derivative, reduces peritoneal adhesions and increases peritoneal fibrinolysis in rats. 1677 72


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