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)

Experimental and clinical research supports a direct link between activation of the renin-angiotensin system and production of plasminogen activator inhibitor-1 (PAI-1), the primary physiologic inhibitor of tissue plasminogen activator. Several studies have reported higher PAI-1 levels in individuals carrying the deletion (D) allele of the angiotensin-converting enzyme (ACE) gene. We investigated the association between ACE genotypes and plasma PAI-1 levels in a family study of 577 women and 428 men from four US communities. Participants were between 25 and 84 years of age without evidence of coronary heart disease (CHD). Mean geometric plasma PAI-1 levels adjusted for ethnicity were 17.4, 17.9, and 18.1 ng/ml in participants with the DD, insertion-deletion (ID), and II genotypes, respectively (P = 0.89 for difference). We found no associations between ACE I/D genotypes and plasma PAI-1 antigen concentrations in a subset of participants without major CHD risk factors (hypertension, hypercholesterolemia, overweight, smoking, diabetes) or in a small sample of African-Americans. Our findings suggest that the ACE insertion/deletion polymorphism has relatively little, if any, influence on circulating PAI-1 levels in the population at large.
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PMID:Lack of association between the angiotensin-converting enzyme insertion/deletion polymorphism and plasminogen activator inhibitor-1 antigen levels in the National Heart, Lung, and Blood Institute Family Heart Study. 1099 95

Sixteen Japanese patients of both sexes aged 46-78 years with essential hypertension were studied at the cardiac clinic of the Department of Cardiology, Shizuoka General Hospital, Shizuoka, Japan. Serum lipids, lipoproteins, plasma fibrinolytic parameters, renin and noradrenaline were determined before and after 3 months of cilnidipine treatment. Systolic and diastolic blood pressures and heart rate were reduced while renin and noradrenaline levels remained unchanged after cilnidipine treatment. Total cholesterol and tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1) and t-PA-PAI-1 complex were reduced. Changes in the other lipids, lipoproteins and fibrinolytic parameters were not significant after cilnidipine treatment. A negative correlation was found between low-density lipoprotein cholesterol and t-PA antigen levels after cilnidipine treatment. In conclusion, cilnidipine was effective for the treatment of hypertension and did not cause reflex tachycardia in Japanese patients. Cilnidipine treatment produced a beneficial lipid profile (decrease in total cholesterol), but did not show a consistent effect on fibrinolytic parameters in hypertensive patients. The metabolic interaction between beneficial lipid changes and fibrinolysis will be of value to better our understanding of the antiatherogenic effects of cilnidipine treatment in hypertensive patients.
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PMID:Effects of cilnidipine on lipids, lipoproteins and fibrinolytic system in hypertensive patients. 1110 11

Experimental, genetic and clinical evidence suggests that the renin-angiotensin-aldosterone system (RAAS) may participate in the pathogenesis of thromboembolic cardiovascular disorders such as coronary heart disease. This interrelationship may involve mechanisms other than changes in arterial blood pressure. In addition to various possible interactions, accumulating evidence suggests that the RAAS is involved in the regulation of the fibrinolytic system. Several recent studies have shown that stimulation of the RAAS may be associated with an activation of plasminogen activator inhibitor 1 (PAI-1). Since profibrinolytic factors (especially tissue plasminogen activator [t-PA]) remain unchanged, increased activity of the RAAS may thus alter the fibrinolytic balance towards a decreased fibrinolytic activity. These findings may be of special importance for a variety of clinical problems such as the long-term effect of a low NaCl-intake on cardiovascular morbidity and mortality and the possible value of drugs indirectly or directly interfering with the RAAS such as diuretics, ACE-inhibitors and angiotensin II Type 1 (AT1) receptor antagonists.
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PMID:[Renin-angiotensin-aldosterone system and fibrinolysis]. 1119 56

Previous studies have shown that angiotensin II stimulates the synthesis of plasminogen activator inhibitor-1 in cultured vascular cells, which suggests that activation of the renin-angiotensin system may impair fibrinolysis. We have investigated the effects of angiotensin II and of valsartan, a recently developed angiotensin II antagonist that is highly specific and selective for the angiotensin II subtype 1 receptor, on plasminogen activator inhibitor-1 secretion by smooth muscle cells isolated from rat and human vessels. Angiotensin II induced a time- and concentration-dependent increase of plasminogen activator inhibitor activity in supernatants of rat aortic cells, which reached a plateau after 6 hours of incubation with 100 nmol/L angiotensin II (2.4+/-0.6-fold over control value; P:<0.001). The angiotensin II-induced plasminogen activator inhibitor activity was inhibited, in a concentration-dependent manner, by valsartan with an IC(50) value of 21 nmol/L. Valsartan fully prevented the angiotensin II-induced increase in plasminogen activator inhibitor-1 protein and mRNA. Furthermore, angiotensin II doubled the secretion of plasminogen activator inhibitor-1 by smooth muscle cells obtained from human umbilical and internal mammary arteries, and valsartan fully prevented it. Angiotensin II did not affect the secretion of tissue plasminogen activator antigen by any of the cell systems tested. Thus, valsartan effectively inhibits angiotensin II-induced plasminogen activator inhibitor-1 secretion without affecting that of tissue plasminogen activator in arterial rat and human smooth muscle cells.
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PMID:Effect of valsartan on angiotensin II-induced plasminogen activator inhibitor-1 biosynthesis in arterial smooth muscle cells. 1124 25

Plasminogen activator inhibitor type-1 (PAI-1) is known to contribute to thrombus formation and to the development and the clinical course of acute and chronic cardiovascular disease, as well as of other arterial and venous thromboembolic diseases. Recently, an important role of elevated pretreatment levels of PAI-1 for failure of thrombolytic therapy of acute myocardial infarction has been discussed. PAI-1 plasma levels depend on the one hand on gene regulation but are related on the other hand to known risk factors of atherosclerosis like insulin resistance, diabetes or hypertriglyceridemia, respectively. Furthermore, an activated renin-angiotensin-aldosterone system (RAAS) significantly contributes to the upregulation of PAI-1 concentration via a receptor-mediated mechanism. In accordance to the known mechanisms of regulation of PAI-1 plasma levels, the use of specific agents like antidiabetic drugs, fibrates, statins, ACE inhibitors and angiotensin II type-1 receptor-blockers may contribute to the downregulation of circulating PAI-1 and, therefore, increase the fibrinolytic capacity and consecutively counteract the thrombotic tendency. To further improve the efficacy of thrombolytic therapy, a PAI-1 resistant variant of t-PA, TNK-t-PA, has been developed and is now available for acute myocardial infarction.
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PMID:Plasminogen activator inhibitor type-1 in cardiovascular disease. Status report 2001. 1156 64

Disorders in the fibrinolytic and renin-angiotensin-aldosterone systems and excessive extracellular matrix (ECM) deposition are determinant factors in several pathologic manifestations of vascular and cardiac tissue. We used primary human vascular smooth muscle cells (VSMC) and studied the effects of losartan on angiotensin II (Ang II)-mediated (a) DNA synthesis, (b) secretion of tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1), (c) secretion of matrix metalloprotease-2 (MMP-2) activity and tissue inhibitors of MMPs (TIMPs), and (d) synthesis of glycosaminoglycans. VSMC cultures, established from human pulmonary arteries, were treated with Ang II (0.1 nM -1 microM ) and/or losartan (0.1-10 microM ), for 24 or 48 h. DNA synthesis was assessed by incorporation of 3 H-thymidine into VSMC, secreted tPA, PAI-1, and TIMPs by enzyme-linked immunosorbent assay, MMP-2 activity by gelatin zymography, and glycosaminoglycan synthesis by 3 H-glucosamine incorporation. Ang II (1 microM ) enhanced DNA synthesis and secretion of PAI-1 and glycosaminoglycans and decreased secretion of MMP-2 activity and tPA, whereas it had no effect on secretion of TIMPs and glycosaminoglycans associated with cell layers. The Ang II-mediated effects were reversed by losartan, in a concentration-dependent manner. Losartan alone increased secretion of tPA, MMP-2 activity, and TIMPs and decreased secretion of PAI-1. These results indicate that AT 1 receptors are implicated in Ang II-mediated disorders of fibrinolysis and excessive ECM deposition by VSMC.
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PMID:Losartan inhibits the angiotensin II-induced modifications on fibrinolysis and matrix deposition by primary human vascular smooth muscle cells. 1160 18

Disclosure of a specific prothrombotic/antifibrinolytic state by determination of plasminogen activator inhibitor type 1 (PAI-1), tissue-type plasminogen activator (t-PA), and t-PA/PAI-1 complex levels in plasma may help to define patients at high risk of developing acute coronary syndromes. According to the mechanisms of PAI-1 up-regulation, i.e. genetic factors, an activated renin-angiotensin-aldosterone system, and other atherosclerotic risk factors (hypertriglyceridemia, insulin resistance), PAI-1 plasma levels might be reduced by the action of antidiabetic drugs, fibrates, statins, as well as by inhibitors of the renin-angiotensin-aldosterone system, and this effect might contribute to the anti-atherosclerotic and antithrombotic actions of these drugs. Moreover, PAI-1 resistant fibrinolytic agents may be beneficial in thrombolytic therapy of acute myocardial infarction.
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PMID:Defective fibrinolytic states as triggers of myocardial infarction: the cardiologist's view. 1166 90

Recent studies have defined a link between the renin-angiotensin-aldosterone system and fibrinolysis. The present study tests the hypothesis that endogenous aldosterone regulates plasminogen activator inhibitor-1 (PAI-1) production in humans. Hemodynamic parameters, PAI-1 and tissue-type plasminogen activator (t-PA) antigen, potassium, PRA, angiotensin II, and aldosterone were measured in nine male hypertensive subjects after a 3-wk washout, after 2 wk of hydrochlorothiazide (HCTZ; 25 mg plus 20 mmol KCl/d), and after 2 wk of spironolactone (100 mg/d plus KCl placebo). Spironolactone (P = 0.04), but not HCTZ (P = 0.57 vs. baseline; P = 0.1 vs. spironolactone), significantly lowered systolic blood pressure. Angiotensin II increased from baseline during both HCTZ (P = 0.02) and spironolactone (P = 0.02 vs. baseline; P = 0.19 vs. HCTZ) treatments. Although both HCTZ (P = 0.004) and spironolactone (P < 0.001 vs. baseline) increased aldosterone, the effect was greater with spironolactone (P < 0.001 vs. HCTZ). HCTZ increased PAI-1 antigen (P = 0.02), but did not alter t-PA antigen. In contrast, there was no effect of spironolactone on PAI-1 antigen (P = 0.28), whereas t-PA antigen was increased (P = 0.01). There was a significant correlation between PAI-1 antigen and serum aldosterone during both baseline and HCTZ study days (r(2) = 0.57; P = 0.0003); however, treatment with spironolactone abolished this correlation (r(2) = 0.13; P = 0.33). This study provides evidence that endogenous aldosterone influences PAI-1 production in humans.
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PMID:Spironolactone abolishes the relationship between aldosterone and plasminogen activator inhibitor-1 in humans. 1183 65

Thrombus formation and degradation is partly due to a complex interplay between tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1). There is accumulating evidence that plasma levels of t-PA and PAI-1 may be influenced by an interaction between the fibrinolytic and renin-angiotensin systems. The goal of this study was to conduct an exploratory data analysis to determine whether there is evidence that the relationship (i.e. correlation) between plasma t-PA and PAI-1 is influenced by interactive effects of the angiotensin converting enzyme (ACE) insertion/deletion (I/D) and plasminogen activator inhibitor 1 (PAI-1) 4G/5G polymorphisms in a sample of 50 unrelated African Americans and 117 unrelated Caucasians. In a single-locus analysis, no evidence for heterogeneity of plasma t-PA and PAI-1 correlations among either ACE I/D or PAI-1 4G/5G genotypes was detected. However, using the combinatorial partitioning method for exploratory data analysis, we identified evidence that is suggestive of heterogeneity of plasma t-PA and PAI-1 correlations among multilocus ACE I/D and PAI-1 4G/5G genotypes in African American females, Caucasian females, Caucasian males, but not African American males. From these results, we propose as a working hypothesis that the correlation between plasma t-PA and PAI-1 may be dependent on epistatic effects of the ACE I/D and PAI-1 4G/5G polymorphisms. This study supports the idea that interactions between the fibrinolytic and renin-angiotensin systems play an important role in the genetic architecture of plasma t-PA and PAI-1.
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PMID:The relationship between plasma t-PA and PAI-1 levels is dependent on epistatic effects of the ACE I/D and PAI-1 4G/5G polymorphisms. 1212 88

Regulation of vascular tone by the endothelium is abnormal in patients with heart failure and contributes to the characteristic peripheral vasoconstriction and increased afterload. This endothelial dysfunction is mediated through several endothelium-derived factors, including nitric oxide; there is an important interplay between the endothelium and the renin angiotensin system. The benefits of ACE inhibition in heart failure relate, in part, to a reduction in ischemic events which may be mediated by improvements in endothelial function and the endothelium derived fibrinolytic parameters: tissue plasminogen activator (t-PA) and its inhibitor, plasminogen activator inhibitor type 1 (PAI-1). In addition to potential improvements in the regulation of vasomotion, ACE inhibitor therapy may increase bradykinin induced t-PA release and/or reduce angiotensin II mediated PAI-1 release. Recent evidence suggests that both angiotensin II type 1 receptor (AT(1)) antagonism and ACE inhibition improve basal fibrinolytic parameters in patients with heart failure which may facilitate the acute endogenous fibrinolytic response. 1999 by CHF, Inc.
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PMID:The renin angiotensin system and endothelial dysfunction in chronic heart failure: role of endogenous fibrinolysis. 1218 94


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