Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.68 (tissue plasminogen activator)
 11,311 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This case report describes a 48-year-old woman patient with variant angina who died because of severe myocardial ischemia and cardiogenic shock, in spite of chronic therapy with nitrates and calcium-antagonists and acute intravenous administration of nitrates, calcium-antagonists and tissue-type plasminogen activator. Her Holter monitoring showed a reduction of time domain measures of heart rate variability. The hemodynamic study exhibited a normal ventriculography and angiographically normal epicardial coronary arteries. The provocative testing, performed (during intravenous therapy with nitrates and diltiazem) by intracoronary injection of progressively increasing doses of ergonovine, induced only a mild vasoconstriction of proximal left anterior descending artery, without symptoms or ST-T segment changes. This case reminds us that variant angina can be a lethal disease, confirms that a negative result of intracoronary ergonovine testing performed during intravenous therapy with nitrates and calcium-antagonists does not assure the prevention of new episodes during chronic oral therapy with the same drugs, suggests a possible prognostic value of the reduction of heart rate variability indexes and shows an unusual response to nitrate administration.
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PMID:An uncommon case of variant angina. 1054 36

We have used delayed-type hypersensitivity (DTH) responses to probe the mechanisms of drug-induced cardiac allograft acceptance in mice. DBA/2-->C57BL/6 cardiac allograft recipients treated transiently with gallium nitrate accept their grafts for >90 days and fail to display DBA/2-reactive DTH responses. These DTH responses are restored when anti-TGF-beta Abs are included at the challenge site, and cell depletion studies showed that this DTH inhibition is mediated by CD4+ cells. Real-time PCR analysis revealed that allograft acceptor mice produce no more than background levels of TGF-beta mRNA at DTH challenge sites. This suggests that DTH regulation in allograft acceptor mice may involve TGF-beta activation, rather than TGF-beta production. The protease, plasmin, can activate TGF-beta, and activated T cells can express a receptor for the plasmin-producing enzyme urokinase-type plasminogen activator (uPA), and can also produce both uPA and tissue-type plasminogen activator (tPA). We observed that Abs to tPA or uPA can replace anti-TGF-beta mAb for the restoration of donor-reactive DTH responses in allograft acceptor mice. Histologic analysis revealed that accepted cardiac allografts express uPA, tPA, and active TGF-beta, whereas accepted cardiac isografts express only tPA, but not uPA or activated TGF-beta. These data demonstrate that local tPA and uPA contribute to DTH regulation in allograft acceptor mice and suggest that these elements of the fibrinolytic pathway are used to control donor-reactive cell-mediated immunity in allograft acceptor mice.
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PMID:Mechanisms of graft acceptance: evidence that plasminogen activator controls donor-reactive delayed-type hypersensitivity responses in cardiac allograft acceptor mice. 1079 71

Endothelial dysfunction with atherosclerosis is a recognized complication of uremic patients. The hypoalbuminemia of peritoneal dialysis (PD) patients can induce a hypercoagulable and atherogenic state. In this study, we investigated the role played by malnutrition-inflammation syndrome on endothelial function markers in PD patients. We measured markers of nutrition [normalized protein catabolic rate (nPCR), albumin, prealbumin, insulin-like growth factor 1 (IGF-1), transferrin, and cholesterol], markers of endothelial damage and function [tissue-type plasminogen activator (tPA), thrombomodulin (TM), von Willebrand factor (vWF), and NO3 (representing NO)], markers of a coagulable state [fibrinogen and plasminogen activator inhibitor 1 (PAI-1)], markers of inflammation [tumor necrosis factor alpha (TNF alpha) and C-reactive protein (CRP)], and other endothelial injury factors [lipoprotein(a) [Lp(a)] and homocysteine]. We also performed an endothelial stimulation test consisting of right-arm venous occlusion (VO) for 10 minutes. The patients were divided into four groups according to their clinical atherosclerotic score (CAS). We studied 45 clinically stable PD patients. At baseline, statistically significant negative linear correlations were found between albumin and age (r = -0.54, p < 0.05), albumin and vWF post-VO (r = -0.54, p < 0.05), and albumin and TM (r = -0.36, p < 0.05), which are endothelial damage markers and prothrombotic factors. A positive linear correlation was seen between albumin and NO3 post-VO (r = 0.48, p < 0.05), indicating a high vasodilatation capacity. C-Reactive protein and TNF alpha showed a positive linear correlation (r = 0.5, p < 0.01). Similarly, TNF alpha showed a positive linear correlation with cardiovascular risk markers such as fibrinogen (r = 0.79, p < 0.01), PAI-1 (r = 0.44, p < 0.05), and homocysteine (r = 0.37, p < 0.05). Creatinine clearance showed a negative linear correlation with TM (r = -0.36, p < 0.05). Patients with albumin < 4 g/dL showed a lower tPA ratio, lower NO3, and a higher CRP, TNF alpha, and Lp(a) than did patients with albumin > 4 g/dL [tPA ratio: 2.1 +/- 1.56 (n = 29) vs. 2.6 +/- 2.3 (n = 16), p < 0.05; NO3: 47 +/- 27 micrograms/mL vs. 69 +/- 33 micrograms/mL, p < 0.05; CRP: 1.8 +/- 3 mg/dL vs. 1.1 +/- 1.6 mg/dL, p < 0.05; TNF alpha: 44.4 +/- 16 pg/mL vs. 36.6 +/- 21.4 pg/mL, p < 0.05; Lp(a): 55 +/- 39 mg/dL vs. 33 +/- 21 mg/dL, p < 0.05]. Patients with a worse CAS showed higher homocysteine levels and lower albumin values. Those relationships were maintained in both periods of the study. We found no relationships between dialysis dose and endothelial function markers. In conclusion, malnutrition-inflammation syndrome may contribute to endothelial dysfunction and, consequently, to prothrombotic and proatherogenic processes in PD patients.
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PMID:Malnutrition-inflammation syndrome is associated with endothelial dysfunction in peritoneal dialysis patients. 1476 71

Transgenic Laminaria japonica gametophytes producing a recombinant tissue-type plasminogen activator (rtPA) protein, which is an effective third-generation thrombolytic agent for acute myocardial infarction (AMI), were cultured in an illuminated bubble column bioreactor. A maximum final dry cell weight of 1120 mg l(-1) was obtained in batch culture with an initial dry cell weight of 126 mg l(-1) and with aeration rate of 1.2 l air min(-1 )l(-1) culture, nitrate at 1.5 mM: and phosphate at 0.17 mM: . The yield of rtPA was 56 microg g(-1) dry cell wt. This is the first report regarding cultivation of a transgenic macroalga in a bioreactor.
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PMID:Suspension culture of gametophytes of transgenic kelp in a photobioreactor. 1613 48

Bradykinin (BK) liberates nitric oxide, prostacyclin, and tissue plasminogen activator from endothelial cells. We hypothesized that BK B2 receptor knockout (KO) mice (BKB2R(-/-)) have increased thrombosis risk. Paradoxically, the BKB2R(-/-) mice have long bleeding times and delayed carotid artery thrombosis, 78 +/- 6.7 minutes, versus 31 +/- 2.7 minutes in controls. The mechanism(s) for thrombosis protection was sought. In BKB2R(-/-) plasma coagulation, fibrinolysis and anticoagulant proteins are normal except for an increased prekallikrein and decreased factor XI. BKB2R(-/-) mice have elevated BK 1-5 (160 +/- 75 fmol/mL, vs 44 +/- 29 fmol/mL in controls) and angiotensin II (182 +/- 41 pg/mL, vs 49 +/- 7 pg/mL in controls). Ramipril treatment shortens vessel occlusion time. BKB2R(-/-) mice have elevated plasma 6-keto-PGF1alpha (666 +/- 232 ng/mL, vs 23 +/- 5.3 ng/mL in controls) and serum nitrate (61 +/- 5.3 microM, vs 24 +/- 1.8 microM in controls). Treatment with L-NAME (NG-mono-methyl-L-arginine ester) or nimesulide shortens the thrombosis time. BKB2R(-/-) mice have increased angiotensin receptor 2 (AT2R) mRNA and protein expression. Treatment with an AT2R antagonist, PD123 319, normalizes the thrombosis time and nitrate and 6-keto-PGF1alpha. The long bleeding times in BKB2R(-/-) mice also correct with L-NAME and nimesulide therapy. In BKB2R(-/-) mice, angiotensin II binding to an overexpressed AT2R promotes thromboprotection by elevating nitric oxide and prostacyclin. These investigations indicate a pathway for thrombosis risk reduction via the plasma kallikrein/kinin and renin angiotensin systems.
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PMID:Bradykinin B2 receptor knockout mice are protected from thrombosis by increased nitric oxide and prostacyclin. 1651 58

Coagulation abnormalities have been implicated in the pathogenesis of sepsis and organ dysfunction. Nitric oxide (NO) is regarded as a critical mediator of many vascular pathologies, including sepsis. However, limited evidence is available to document a relationship between NO generated by inducible NO synthase (iNOS) and hemostatic abnormalities in sepsis. Therefore, we evaluated the effects of selective iNOS inhibition on markers of endothelial and coagulation homeostasis in a clinically relevant model of porcine bacteremia induced and maintained for 24 hours (h) with a continuous infusion of live P. aeruginosa. After 12 h of sepsis, animals received either vehicle (Control, n=7) or continuous infusion of selective iNOS inhibitor L-NIL (n=7). Before as well as 12, 18 and 24 h after starting P. aeruginosa following variables related to i) endothelial dysfunction (von Willebrand factor [vWf]; tissue plasminogen activator activity [t-PA]; ii) coagulation (thrombin-antithrombin complexes [TAT]; platelet count); iii) fibrinolysis (t-PA activity, activity of plasminogen activator inhibitor type 1 (PAI-1 act); and iv) oxidative/nitrosative stress (isoprostanes, nitrate/nitrite levels) were measured. L-NIL inhibited sepsis-induced increase in plasma nitrate/nitrite and isoprostanes concentrations, prevented hypotension and acidosis. L-NIL significantly attenuated sepsis-induced rise in plasma vWF and TAT. P. aeruginosa-induced drop in t-PA activity was blunted by iNOS inhibition, while increased PAI-1 and reduced platelet count were not reversed by the treatment. In conclusion, selective iNOS inhibition was associated with attenuation of sepsis-induced coagulation and endothelial dysfunction suggesting the interplay between mediators of vascular system and hemostatic balance. Reduction of oxidative stress probably contributes to the beneficial effects afforded by iNOS blockade.
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PMID:Coagulation and endothelial dysfunction during longterm hyperdynamic porcine bacteremia--effects of selective inducible nitric oxide synthase inhibition. 1726 61

Kidney transplantation is associated with increased cardiovascular risk. Endothelial dysfunction and vascular inflammation contribute to negative outcome. In experimental models, mineralocorticoid receptor antagonists improved endothelial function and reduced inflammation. The present study tested the hypothesis that the mineralocorticoid receptor antagonist spironolactone improves endothelial function and reduces vascular inflammation in renal transplant patients. Eighty prevalent renal transplant patients from an ongoing, double-blind randomized placebo-controlled trial were included. Paired plasma samples before and after 1 yr of treatment (n = 39 in the spironolactone-treated group and 41 in the placebo-treated group) were used to determine markers of endothelial dysfunction (nitrite, nitrate, cGMP, arginine, citrulline, ornithine, asymmetric dimethylarginine, symmetric dimethylarginine, NG-monomethyl-l-arginine, von Willebrand factor, tissue-type plasminogen activator antigen, and plasminogen activator inhibitor 1 antigen) and markers of inflammation (intercellular adhesion molecule, vascular adhesion molecule, high-sensitivity C-reactive protein, and serum amyloid protein A). The median time since the transplantation was 4.6 (0.12-22.3) yr in the spironolactone-treated group and 2.1 (0.17-13.9) yr in the placebo-treated group (P > 0.05). Spironolactone increased plasma aldosterone (P < 0.001) and K+ (P < 0.001). Blood pressure did not change significantly. No significant differences were detected between groups in any of the measured markers of endothelial dysfunction or inflammation except in the subgroup analysis of patients with diabetes, where spironolactone decreased nitrite compared with placebo. In this study, mineralocorticoid receptor antagonism did not improve biomarkers of endothelial dysfunction or vascular inflammation in prevalent renal transplant patients. Further studies are needed to evaluate the potential beneficial effect of early or late mineralocorticoid receptor antagonism on vascular outcomes in renal transplant patients.
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PMID:Effect of spironolactone for 1 yr on endothelial function and vascular inflammation biomarkers in renal transplant recipients. 3116 6


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