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)

The endothelium participates in haemostasis, inflammation, blood pressure regulation and other physiological systems. Consequently, endothelial dysfunction has been related to hypertension, thrombosis and atherosclerosis. Both von Willebrand factor (vWF) and tissue-type plasminogen activator (t-PA) are synthesized by the endothelium and their plasma levels increased during endothelium activation or injury. So far, they are well-known markers of endothelial cell function. Many circumstances activate or damage the endothelium, such as viruses, bacterium and inflammation. Circulating vWF and t-PA were studied in 92 unselected human immunodeficiency virus-1 (HIV-1)-infected patients [27 patients with and 65 patients without acquired immunodeficiency syndrome (AIDS)] and correlated with plasma levels of pro-inflammatory cytokines (tumour necrosis factor-alpha, interleukin-6), viral load, CD4 T-cell count and infectious status. HIV-1-infected patients had significantly higher plasma levels of vWF (152 versus 90%), tumour necrosis factor-alpha (31.3 versus 9.0 pg/ml) and interleukin-6 (3.5 versus 1.9 pg/ml) but not t-PA (5.9 versus 4.2 ng/ml) than the control group. These two endothelial markers correlated significantly with viral load and interleukin-6 levels in HIV-1-infected patients. The highest levels of vWF and t-PA were found in patients with AIDS. In conclusion, endothelial cell perturbation is present in HIV infection and may be a consequence of different mechanisms such as viral load, cytokines and advanced diseases.
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PMID:Viral load and disease progression as responsible for endothelial activation and/or injury in human immunodeficiency virus-1-infected patients. 1254 23

Impaired fibrinolysis is a common finding in obese humans. This condition is now considered as an established risk factor for thromboembolic complications. Furthermore, obesity is characterized by a specific pattern of circulating concentrations of fat-cell products interleukin-6 (IL-6), leptin, and adiponectin. The aim of our study was to investigate the relationship between these proteins and selected variables of the fibrinolytic system in 74 mildly hypertensive, overweight subjects. Circulating IL-6 and leptin levels showed a positive association with BMI (r = 0.24, p = 0.04 and r = 0.70, p < 0.0001), whereas adiponectin was not correlated to BMI. Interestingly, IL-6 was also positively associated with t-PA/PAI-1 complexes after adjustment for BMI and other anthropometric variables. Leptin was positively correlated with PAI-1 activity and antigen (r = 0.32, p = 0.006 and r = 0.37, p < 0.001, respectively) and negatively with t-PA activity (r = -0.27, p = 0.03). However, these associations lost significance after correction for BMI or HOMA, an insulin sensitivity index. In contrast, adiponectin levels were independently and negatively correlated with PAI-1 antigen (r = -0.26, p = 0.04, after correction for BMI). In conclusion, our study provides further evidence that IL-6, leptin, and adiponectin are associated with impaired fibrinolysis in overweight hypertensive humans.
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PMID:Relationship between IL-6, leptin and adiponectin and variables of fibrinolysis in overweight and obese hypertensive patients. 1266 Aug 78

In the present study, we compared the effect of atorvastatin (1 mg.kg(-1).day(-1)) and quinapril (0.5 mg.kg(-1).day(-1)) alone or in combination on inflammatory markers, endothelial function, intimal thickening and fibrinolytic balance in rabbits fed with either a control diet or a diet containing 1% (v/v) cholesterol for 12 weeks. Atorvastatin alone or in combination partially prevented the increase in cholesterol plasma levels observed in rabbits fed with the cholesterol-rich diet, but did not modify blood pressure levels. Quinapril administration did not alter any of these parameters in any group. Hypercholesterolaemia increased plasma levels of interleukin-1beta, interleukin-6, interferon-gamma and C-reactive protein, reduced acetylcholine-induced relaxation and produced intimal thickening. Likewise, atherosclerotic rabbits had reduced plasma tissue-type plasminogen activator activity and D-dimer levels and an increase in plasminogen-activator inhibitor-1 activity. Both drugs enhanced acetylcholine-induced relaxation, reduced intimal thickening and improved fibrinolytic balance in atherosclerotic rabbits in a similar manner. Their combination did not induce additive effects on these parameters. However, only the combination of both drugs was able to prevent the increase in inflammatory markers induced by hypercholesterolaemia. In summary, these data suggest that quinapril and atorvastatin had comparable beneficial effects on the alterations of vascular function and structure as well as fibrinolytic balance in atherosclerotic rabbits. In addition, the combination of atorvastatin and quinapril exerts a synergistic effect on inflammatory markers, which individual treatment, at the doses used, was not able to modify.
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PMID:Synergistic effect of angiotensin-converting enzyme (ACE) and 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibition on inflammatory markers in atherosclerotic rabbits. 1284 17

Data on the dural invasiveness of pituitary adenomas have been correlated to the expression of matrix metalloproteinases (e.g. MMP-9). Serine proteases have not yet been investigated in human pituitary adenomas. In this study, paraffin-embedded material from 84 human pituitary adenomas (acromegaly n=18, Cushing's disease n=21, prolactinoma n=18, thyroid-stimulating hormone-secreting adenoma n=1, nonsecreting adenoma n=26) and 9 nontumourous anterior pituitary lobes (obtained from patients with prostate cancer) was immunohistochemically analysed for expression of MMP-2, MMP-9, tissue inhibitor of metalloproteinases-2 (TIMP-2), urokinase-type plasminogen activator (uPA), uPA receptor (uPAR), tissue-type plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), and interleukin-6 (IL-6). Cavernous sinus invasion was determined by assessment of preoperative magnetic resonance imaging and intraoperative inspection (invasive n=50, noninvasive n=34). In pituitary adenomas, reactions were positive (diffuse expression) to MMP-2 (74% of cases), MMP-9 (49%), TIMP-2 (88%), uPA (89%), uPAR (90%), tPA (69%), and PAI-1 (87%). A weak expression of IL-6 was found in 12% of the adenomas. All reactions were positive (focal expression) in every sample of anterior lobe tissue, except for uPA (negative in 3 out of 9 cases), and IL-6 (faintly positive in 5 out of 8 cases). Adenomas showed remarkably greater expression of uPA than anterior lobe tissue (Chi-square P<0.05). Nonsecreting adenomas exhibited a stronger tendency towards overexpression of uPA in invasive tumours when compared to noninvasive adenomas (Chi-square P=0.053). We found no correlation of MMP-9 expression and tumour invasion. TIMP-2 was overexpressed in noninvasive as compared to invasive adenomas (Chi-square P<0.05). The interrelationship between MMPs and serine proteinases in pituitary adenomas remains to be elucidated. From our data, a correlation between IL-6 and an activation of MMP-9 cannot be proven. The uPA-system may, however, play a role in dural invasion of pituitary adenomas.
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PMID:Expression of serine proteases and metalloproteinases in human pituitary adenomas and anterior pituitary lobe tissue. 1290 90

Background: An association between Chlamydia pneumoniae (Cp) infection and coronary heart disease (CHD) has already been reported. We investigated the relationship between Cp infection and other risk factors in CHD patients, as well as the effects of azithromycin treatment. Methods: We studied 38 patients with Cp infection (Cp-pos) and 15 without (Cp-neg). Cp-pos patients had, both at inclusion and 2 years prior to inclusion, elevated Cp-specific IgA-antibodies, with or without the presence of pharyngeal Cp by polymerase chain reaction (PCR) detection. Blood was analyzed for Cp-antibodies, interleukin-6, interleukin-1 receptor antagonist (IL-1ra), CRP, orosomucoid, fibrinogen, leukocytes, PAI-1, tPA, von Willebrand factor (vWf), platelet count and aggregation, and lipids. Cp-pos patients were randomized to placebo or oral azithromycin, 500 mg on day 1 and then 250 mg/day for 4 days, with repeated therapy after 3 weeks. Blood was taken immediately, as well as 3 months and 2 years after therapy. Results: CRP and IL-1ra levels were higher in Cp-pos than in Cp-neg patients: median, interquartile range 8.5 (3.0-20) vs. 2.0 (1.0-3.8) mg/l, and 316 (165-404) vs. 178 (118-195) ng/l, p=0.0006 and p=0.002, and platelet aggregation was lower: 4.8 (2.9-6.4) vs. 8.1 (4.7-11.4) Omega, p<0.05. tPA levels increased in azithromycin-treated patients between entry and 3-month follow-up: mean+/-S.D. 3.7+/-4.2 vs. 1.0+/-2.1 microg/l, p<0.05. Other variables did not differ. Conclusions: Cp infection was associated with increased inflammatory activity and lower platelet aggregability, suggesting that inflammation may be of greater pathophysiological importance than platelet activity in these patients. Although an effect on Cp infection was not shown, azithromycin may have a positive effect on fibrinolysis, as increased levels of tPA were observed in the treatment group.
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PMID:Azithromycin therapy in patients with chronic Chlamydia pneumoniae infection and coronary heart disease: immediate and long-term effects on inflammation, coagulation, and lipid status in a double-blind, placebo-controlled study. 1496 98

This study investigated the contribution of endogenous suppression of fibrinolysis and increased fibrin deposition to intestinal dysfunction and injury in a rat model of intestinal ischemia/reperfusion (I/R), as fibrinolytic inhibition may lead to thrombotic obstructions that compromise microcirculation and promote intestinal injury. Circulatory fibrinolysis was enhanced by intravenous administration of recombinant tissue plasminogen activator (rt-PA) or by inhibition of PAI-I by administration of MA-33H1F7. Coagulation and fibrinolysis parameters obtained from portal blood were correlated to fibrin deposition (determined by anti-rat fibrin antibody staining), intestinal function (glucose/water clearance) and intestinal injury (histological evaluation by Park/Chiu score). Enhanced circulatory fibrinolytic activity, as evidenced by increased portal plasma plasminogen activator activity, elevated fibrin degradation products and decreased levels of PAI-I, did not reduce mucosal fibrin deposition and microthrombosis in postischemic intestinal tissue. Furthermore, rt-PA or anti-PAI-I antibody administration did not attenuate I/R-induced intestinal injury or dysfunction, as demonstrated by intestinal histopathology scores of 4.8+/-0.2 and 4.7+/-0.3 (control I/R group 4.7+/-0.2) and glucose clearances of 47+/-6 and 46+/-9 micro L/min g (control I/R group 30+/-8 micro L/min. g) after 40 minutes of intestinal ischemia and 3 hours of reperfusion, respectively. However, both interventions resulted in decreased levels of interleukin-6, which may indicate fibrin-induced modulation of inflammation. Attempts to enhance the fibrinolytic activity (either by rt-PA or by anti-PAI-I administration), indicated by increased portal plasma levels of released FDP, failed to decrease mucosal fibrin deposition and to attenuate intestinal I/R injury. Based on our observations and previous reports, the contribution of suppressed endogenous fibrinolysis to microcirculatory fibrin deposition and I/R-injury may be of limited importance.
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PMID:Enhancement of endogenous fibrinolysis does not reduce local fibrin deposition, but modulates inflammation upon intestinal ischemia and reperfusion. 1498 25

The effects of cerivastatin and fenofibrate on proteins involved in haemostasis and on markers of inflammation were investigated in otherwise healthy middle-aged males with combined hyperlipidemia. Besides classical risk factors, other so-called novel risk factors for coronary artery disease are seen to be playing an increasingly important role in the development and progression of atherosclerosis. Thirty-eight males, aged 49 +/-5 years were randomised to 12 weeks treatment either with cerivastatin at a daily dose of 0.2 mg to 0.4 mg to achieve the LDL cholesterol goal of <3.0 mM, or with fenofibrate 250 mg daily. Fasting serum lipids, homocysteine, total and free tissue factor pathway inhibitor (TFPI), plasminogen activator inhibitor (PAI-1) and tissue plasminogen activator (t-PA) antigen and activity, C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were measured. No change in homocysteine level was observed in the cerivastatin group, while after fenofibrate administration it increased (p <0.0001). Total TFPI decreased significantly after cerivastatin (p = 0.002), but not after fenofibrate. Free TFPI did not decrease after either drug. Neither drug affected (t-PA) antigen and activity, while fenofibrate increased PAI-1 antigen (p <0.05) and activity (p <0.05). Cerivastatin decreased serum CRP values by 49.5% (p = 0.001), and fenofibrate by 29.8% (p = 0.03). The decreases of CRP in the two groups differed significantly (p = 0.04). IL-6 levels decreased significantly in the fenofibrate group (39%; p <0.0001), but not in the cerivastatin group (15%; p = 0.24) No significant decreases were observed for TNF-alpha. Cerivastatin had neutral effects on fibrinolysis, homocysteine or coagulation. On the other hand, fenofibrate increased PAI-1 antigen and activity and homocysteine, and did not affect coagulation. Both cerivastatin and fenofibrate reduced CRP levels, the decrease being significantly greater after cerivastatin. Fenofibrate also significantly decreased IL-6.
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PMID:Statin and fibrate treatment of combined hyperlipidemia: the effects on some novel risk factors. 1554 43

Clinical trials of postmenopausal hormone therapy (PHT) have found an early increase in cardiovascular events, and have not demonstrated the reduction in coronary heart disease (CHD) predicted from changes in conventional risk factors or found in observational studies, suggesting that PHT may increase coronary risk through other pathways. We compared baseline levels of C-reactive protein (CRP), interleukin-6 (IL-6), sICAM-1, tissue plasminogen activator antigen (tPA-antigen), D-dimer, homocysteine, triglycerides, total-, HDL- and LDL- cholesterol in 304 cases with incident CHD and 304 controls, according to self-reported use of PHT. Subjects were selected from the 75,343 participants in the WHI Observational Study without baseline cardiovascular disease or cancer. PHT was associated with higher CRP, HDL and triglycerides, and lower tPA-antigen and homocysteine. CRP was highest in users of unopposed conjugated equine estrogen. Levels of IL-6,sICAM-1,D-dimer and total cholesterol did not differ between PHT users and non-users. Transdermal estrogen users had low levels of D-dimer and CRP. Among users of estrogen plus progestin (EP), CRP, IL-6, tPA-antigen, D-dimer, total cholesterol and triglycerides were higher in women with incident coronary events than controls. Estrogen alone (E) controls shared only the tPA-antigen association, but had higher HDL and lower LDL than E cases. In non-users CRP, tPA-antigen and D-dimer were associated with incident CHD. In summary, risk markers differed by PHT category. Some associations differed between women with and without incident CHD, especially for EP, where inflammatory and thrombotic markers were higher in cases. These associations remain speculative pending confirmation in randomized trials.
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PMID:Baseline associations between postmenopausal hormone therapy and inflammatory, haemostatic, and lipid biomarkers of coronary heart disease. The Women's Health Initiative Observational Study. 1596 96

Heparin cofactor II functions as a physiological inhibitor of thrombin activity. The rate of inactivation of thrombin by heparin cofactor II is increased in the presence of dermatan sulfate, which is produced by fibroblasts or smooth muscle cells. To elucidate the role of heparin cofactor II in the extravascular cells, we induced expression of heparin cofactor II in cultured human fibroblasts or vascular smooth muscle cells using adenovirus-mediated gene transfer. After infection of adenovirus vector, these cells secreted heparin cofactor II protein into culture medium. The expressed heparin cofactor II formed the complex with exogenous thrombin and inhibited the proteolytic activity of thrombin. Expression of heparin cofactor II by infection of adenovirus vector inhibited thrombin-induced tissue-type plasminogen activator and interleukin-6 releases from fibroblasts and thrombin-induced interleukin-6 release from vascular smooth muscle cells. These findings show that fibroblasts and vascular smooth muscle cells expressing heparin cofactor II are resistant to thrombin-induced cellular responses.
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PMID:Adenovirus-mediated expression of heparin cofactor II inhibits thrombin-induced cellular responses in fibroblasts and vascular smooth muscle cells. 1603 21

The interplay between inflammatory and hemostatic mechanisms may play a crucial role in the development and progression of atherosclerosis. The authors evaluated the separate and joint associations of hemostatic and inflammatory variables on peripheral atherosclerotic progression in the Edinburgh Artery Study, a population cohort study of 1,592 men and women aged 55-74 years that started in 1987. Levels of fibrinogen, fibrin D-dimer, von Willebrand factor, tissue plasminogen activator antigen, factor VII, prothrombin fragment 1 + 2, urinary fibrinopeptide A, C-reactive protein, and interleukin-6 were measured at baseline. Arm and ankle blood pressures were measured, and atherosclerotic progression was assessed by computing ankle brachial index (ABI) at baseline (1,582 participants) and after 12 years of follow-up (813 participants). Fibrinogen (p = 0.05) and D-dimer (p < or = 0.05) were significantly associated with ABI change independently of baseline ABI and cardiovascular disease risk factors. However, these associations were no longer significant when analyses were adjusted for either C-reactive protein or interleukin-6. Moreover, subjects with higher levels of both D-dimer and interleukin-6 at baseline had the greatest ABI decline. In conclusion, fibrinogen and D-dimer, but not other hemostatic factors, were associated with progressive peripheral atherosclerosis. Since D-dimer and fibrinogen are acute phase reactants, these data support the hypothesis that inflammation is more related to atherosclerosis than is hypercoagulation.
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PMID:Hemostatic factors, inflammatory markers, and progressive peripheral atherosclerosis: the Edinburgh Artery Study. 1635 7


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