Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin (Ang) II is not the only active peptide of the renin-angiotensin system. Several of its degradation products including Ang III (obtained by deletion of the N terminal amino acid), Ang IV (obtained by deletion of the two N terminal amino acids) and Ang II(1-7) (obtained by deletion of the C terminal amino acid) also possess biological functions. These peptides are formed via the activity of several enzymes, aminopeptidase A for Ang III, aminopeptidases A and N for Ang IV, prolylendopeptidase and carboxypeptidases for Ang II(1-7). Ang III possesses most of the properties of Ang II and shares the same receptors. This peptide is particularly important in brain and pituitary physiology and plays a major role in the secretion of arginine vasopressin. Ang IV possesses its own receptors distinct from AT1 and AT2. Some of its effects (for example, stimulation of the synthesis of the type 1 inhibitor of plasminogen activator by endothelial cells) were previously attributed to Ang II. Others are opposed to Ang II effects (renal and cerebral vasodilation). Its role in vascular, renal and cerebral physiology remains to be determined. Ang II(1-7) exhibits direct and indirect effects, the latter resulting from Ang II(1-7)-dependent formation of nitric oxide and vasodilatory prostaglandins. Ang II(1-7) recognizes both specific receptors and AT1 receptors as shown by the partial antagonistic properties of losartan. Ang II(1-7) plays essentially a role in the control of the hydroelectrolytic balance by increasing glomerular filtration rate, urinary output and sodium excretion rate.
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PMID:Active fragments of angiotensin II: enzymatic pathways of synthesis and biological effects. 905 51

In addition to causing vasoconstriction and the retention of salt and water, angiotensin inhibits fibrinolysis, thereby promoting clot formation and protecting against hemorrhage. Activation of the renin-angiotensin system (RAS) can disturb the balance of the fibrinolytic system by stimulating excess production of plasminogen activator inhibitor type 1 (PAI-1) and increasing the risk of thrombotic events. This risk is exacerbated by angiotensin-converting enzyme (ACE)-induced degradation of bradykinin, which normally stimulates production of tissue-type plasminogen activator (t-PA). Modification of the RAS via ACE inhibition may protect against thrombosis by limiting vascular expression of PAI-1 and augmenting bradykinin-induced production of t-PA. Survivors of myocardial infarction treated with an ACE inhibitor have demonstrated a reduction in PAI-1 activity and preservation of the normal ratio of PAI-1 to t-PA. This effect on the fibrinolytic system may contribute to the favorable impact ACE inhibition has been demonstrated to have on the incidence of recurrent myocardial infarction.
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PMID:The renin-angiotensin system and fibrinolysis. 912 16

Angiotensin converting enzyme inhibitors (ACE-I) have been reported to prevent the recurrence of cardiovascular events. The mechanism of this decrease, however, can not be completely explained by anti-hypertensive and anti-hypertrophic effects of ACE-I. To investigate the mechanism of this decrease, we studied the regulation of plasminogen activator inhibitor-1 (PAI-1), tissue type plasminogen activator (TPA), tissue factor (TF), and tissue factor pathway inhibitor (TFPI) by angiotensin II (Ang II) in cultured rat aortic endothelial cells. Ang II increased PAI-1 and TF mRNA expression without affecting that of TPA or TFPI. These inductions were accompanied by increases in PAI-1 and TF activities and were inhibited by a type I Ang II receptor antagonist. The results suggest that Ang II decreases the antithrombotic properties of endothelial cells which increases the chance of thrombosis. Thus, inhibition of the renin-angiotensin system may be beneficial to prevent thrombus formation in treatment of ischemic heart disease.
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PMID:Angiotensin II increases plasminogen activator inhibitor-1 and tissue factor mRNA expression without changing that of tissue type plasminogen activator or tissue factor pathway inhibitor in cultured rat aortic endothelial cells. 924 56

Plasminogen activator inhibitor 1 (PAI-1) is a determinant of vascular events. Subjects in metabolic wards are at high risk for these events. The renin-angiotensin system modulates plasma PAI-1 levels. An insertion (4G)/deletion (5G) polymorphism is involved in the regulation of the circulating levels of PAI-1. We have evaluated the levels of plasma PAI-1 in 208 individuals from our metabolic ward and correlated these levels with the 4G/5G genotype as well as with a genotype (homozygosity for a deletion polymorphism, DD genotype) of the angiotensin-converting enzyme (ACE) gene. Homozygosity for the insertion genotype (5G/5G) was associated with PAI-1 levels lower than those associated with the deletion genotype (4G/4G) (26.2x/:1.6 versus 33.7x/:1.7 ng/mL, P = .036). Plasma PAI-1 levels appeared to depend on the genotype (P = .014) as much as on age (P = .044), t-PA (P = .0001), or triglyceride levels (P = .005). The association between triglycerides and PAI-1 was significant in subjects carrying the 4G/4G and the 4G/5G genotypes (P = .013 and .036, respectively) but not in those with the 5G/5G genotype. When stratified according to PAI-1 and ACE genotypes, individuals homozygous for both deletions (4G/4G-DD genotypes) exhibited higher plasma PAI-1 levels compared with those of individuals without such homozygosities. However, this difference did not reach statistical significance. We conclude that in a group of subjects from a metabolic ward, a 4G/5G polymorphism of the PAI-1 gene exerts effects on plasma PAI-1 antigen levels comparable to those of established determinants. The association between triglycerides and plasma PAI-1 levels is genotype dependent. A trend to a positive interaction between ACE DD and PAI-1 4G/4G in the regulation of circulating plasma PAI-1 levels is present in this setting.
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PMID:Plasminogen activator inhibitor-1 (PAI-1) antigen plasma levels in subjects attending a metabolic ward: relation to polymorphisms of PAI-1 and angiontensin converting enzyme (ACE) genes. 935 75

Deletion polymorphism of angiotensin I-converting enzyme (ACE) gene has been reported to be an independent risk factor for myocardial infarction. Plasminogen activator inhibitor-1 (PAI-1) was proposed to be a link between the renin-angiotensin system and thrombotic risk. This study was undertaken to investigate the possible association between the insertion/deletion (I/D) polymorphism of the ACE gene and plasma PAI-1 levels in 160 patients with mild-to-moderate hypertension. The I/D genotypes were determined by polymerase chain reaction with oligonucleotide primers flanking the polymorphic region in intron 16 of the ACE gene. Baseline levels of PAI-1 antigen and activity and tissue plasminogen activator (t-PA) antigen were determined in fasting morning plasma samples. It was found that patients with homozygote deletion (DD, n = 37) ACE genotype did not have significantly higher plasma levels of PAI-1 antigen (31.2 +/- 15.6 ng/mL v 28.4 +/- 15.1 ng/mL or 27.2 +/- 13.2 ng/mL, P = .42), PAI-1 activity (16.2 +/- 10.6 IU/mL v 14.1 +/- 9.4 IU/ mL or 15.0 +/- 9.9 IU/mL, P = .60), or t-PA antigen (14.6 +/- 6.0 ng/mL v 13.4 +/- 4.9 ng/mL or 14.6 +/- 5.7 ng/mL, P = .40) as compared to those with heterozygote (DI, n = 67) or homozygote insertion (II, n = 56) genotypes. On multiple regression analysis, the ACE genotypes did not appear to be significant predictors for plasma PAI-1 levels and t-PA antigen after adjustment with age, sex, body mass index, plasma triglyceride, cholesterol, and glucose. In conclusion, the results indicated that the I/D polymorphism of the ACE gene was not related to plasma PAI-1 levels in a Chinese population with hypertension. The ACE genotypes may not have a role in influencing the fibrinolysis in hypertension.
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PMID:Plasminogen activator inhibitor-1 and angiotensin I converting enzyme gene polymorphism in patients with hypertension. 952 54

Thromboembolic complications such as ischemic stroke and myocardial infarction are significantly more frequent in patients with arterial hypertension. From the available intervention studies, it appears that pharmacologic treatment of hypertension-at least with diuretics and beta-blockers-may more effectively protect against cerebrovascular as compared to coronary thromboembolic events. Whether other antihypertensive substances provide a more effective protection with respect to cardiac morbidity and mortality is the subject of numerous studies presently underway. These studies will help to answer the question of whether the extent of protection from coronary events during antihypertensive treatment depends on factors beyond blood pressure control. The fibrinolytic system is crucially involved in the pathogenesis of thromboembolic events. One determinant of this system is the balance between plasminogen activators (tissue-type plasminogen activator [t-PA]) and inhibitors (plasminogen activator inhibitor 1 [PAI-1]). Experimental and clinical evidence suggests that at least some of the drugs used in the treatment of hypertension may alter the activity of the fibrinolytic system. Scarce and controversial data with respect to such an interaction exist with respect to diuretics, beta-blockers, and calcium antagonists. In addition, experimental evidence demonstrates that PAI-1 is stimulated by angiotensin II (A II), whereas t-PA is activated by bradykinin. Thus, antihypertensive drugs acting within the renin angiotensin system should exert effects also within the fibrinolytic system. However, results from clinical studies with angiotensin converting enzyme (ACE) inhibitors and A II receptor antagonists do not unequivocally support such a concept. The discrepancy in the results may, at least in part, be explained by studies performed in healthy volunteer subjects showing that ACE inhibition profoundly affected fibrinolysis only during stimulation of the renin angiotensin system by NaCL restriction.
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PMID:Antihypertensive drug treatment and fibrinolytic function. 979 46

The plasminogen activator or fibrinolytic system is an important determinant of vascular homeostasis. It is one of the endogenous defence mechanisms against intravascular thrombus formation, which is implicated in the pathogenesis of myocardial infarction and other acute coronary syndromes. Reduced fibrinolytic activity is a risk factor for ischaemic cardiovascular events. The fibrinolytic system also contributes prominently to vascular remodelling. Fibrinolysis depends on a balance between plasminogen activators, such as urokinase and tissue-type plasminogen activator, and plasminogen activator inhibitor type 1. A growing body of evidence indicates that the renin-angiotensin system can disrupt the equilibrium of the fibrinolytic system both directly and indirectly, with clinical consequences. For example, it appears that angiotensin II and angiotensin i.v. increase the expression of plasminogen activator inhibitor type 1. Pharmacological interruption of the renin-angiotensin system with inhibitors of angiotensin-converting enzyme (ACE) exerts a positive influence on endogenous fibrinolytic balance by blocking the formation of angiotensin II and preventing the degradation of bradykinin. Recent data from our laboratory have provided additional evidence for a link between the renin-angiotensin system and the fibrinolytic system. These findings may help elucidate possible mechanisms by which ACE inhibition exerts vasculoprotective effects and reduces the risk of atherothrombotic events.
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PMID:Fibrinolytic balance, the renin-angiotensin system and atherosclerotic disease. 971 49

Increased plasma renin activity (PRA) has been associated with an increased risk of myocardial infarction (MI), whereas angiotensin-converting enzyme (ACE) inhibition appears to reduce the risk of recurrent MI in patients with left ventricular dysfunction. These observations may be partially explained by an interaction between the renin-angiotensin system (RAS) and fibrinolytic system. To test this hypothesis, we examined the effect of salt depletion on tissue-type plasminogen activator (tPA) antigen and plasminogen activator inhibitor-1 (PAI-1) activity and antigen in normotensive subjects in the presence and absence of quinapril (40 mg BID). Under low (10 mmol/d) and high (200 mmol/d) salt conditions there was significant diurnal variation in PAI-1 antigen and activity and tPA antigen. Morning (8 AM through 2 PM) PAI-1 antigen levels were significantly higher during low salt intake compared with high salt intake conditions (ANOVA, F=5.8, P=0.048). PAI-1 antigen correlated with aldosterone (r=0.56, P<10(-7)) during low salt intake. ACE inhibition significantly decreased 24-hour (ANOVA for 24 hours, F=6. 7, P=0.04) and morning (F=24, P=0.002) PAI-1 antigen and PAI-1 activity (F=6.48, P=0.038) but did not alter tPA antigen. Thus, the mean morning PAI-1 antigen concentration was significantly higher during low salt intake than during either high salt intake or low salt intake and concomitant ACE inhibition (22.7+/-4.6 versus 16. 1+/-3.3 and 16.3+/-3.7 ng/mL, respectively; P<0.05). This study provides evidence of a direct functional link between the RAS and fibrinolytic system in humans. The data suggest that ACE inhibition has the potential to reduce the incidence of thrombotic cardiovascular events by blunting the morning peak in PAI-1.
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PMID:Effect of activation and inhibition of the renin-angiotensin system on plasma PAI-1. 985 58

It has been recently shown that angiotensin II (Ang II) is not the only active peptide of the renin-angiotensin system. Several of its degradation products including Ang III (obtained by deletion of the N terminal amino acids), Ang IV (obtained by deletion of the two N terminal amino acids), and Ang II (1-7) (obtained by deletion of the C terminal amino acid), also possess biological functions. These peptides are formed via the activity of several enzymes: angiotensin--converting enzyme, aminopeptidases A and N, neutral endopeptidase and prolylendopeptidase. Ang III possesses most of the properties of Ang II and shares the same receptors AT1 and AT2. In addition this peptide is particularly important in brain physiology and plays a major role in the secretion of arginine vasopressine. Ang IV possesses its own receptors distinct from AT1 and AT2. Some of its effects (for example, stimulation of the synthesis of the type 1 inhibitor of plasminogen activator by endothelial cells) were previously attributed to Ang II. Others effects, like renal and cerebral vasodilatation, are opposed to Ang II effects. The role of Ang IV in renal physiology remains to be determined. Ang II (1-7) exhibits direct and indirect effects, the latter resulting from Ang II (1-7)-dependent formation of nitric oxide and vasodilatory prostaglandins. Ang II (1-7) potentiates the hypotensive effect of bradykinin and plays also a major role in the control of the hydroelectrolytic balance. It possesses its own receptor: AT1-7, recognizable by (sar1-thr8) Ang II or Sarthran. Finally Ang II (1-7) is converted into Ango II (1-5), by angiotensin-converting enzyme. This peptide is inactive. All of these enzymes, peptides and receptors are present in kidney. Thus the renin-angiotensin system appears to be much more complicated than thought a few years ago, setting the problem of new therapeutic tools for the treatment of hypertension and glomerulosclerosis.
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PMID:[Active metabolites derived from angiotensin II]. 985 79

Inflammatory response in tissue results from a complex network of interactions between inflammatory cells (mast cells, eosinophils, basophils, macrophages) and resident cells belonging to the lung structure (like endothelial cells, fibroblasts, epithelial cells). Among structural cells, endothelial cells play a critical role. The important role of endothelium is also reflected in the fact that it occupies an area exceeding 1000 m2. Thus, endothelium is the largest and the most active paracrine organ in the body, producing potent vasoactive, procoagulant, anticoagulant, and proinflammatory substances. Endothelial cells have four key functions that alter in the process of inflammation: 1 a) Regulation and control of leukocyte traffic through the expression of adhesion molecules (selectins E and P, molecules of immunoglobulin superfamily ICAM-1, ICAM-2, VCAM); 1 b) They are also able to amplify leukocyte activation through the production of proinflammatory cytokines like IL-1, IL-6 and chemokines like IL-8 and RANTES molecules; 2) Regulation of vascular tone by production of PGI-2, EDRF/NO and elements of local renin-angiotensin system; 3) Regulation of local coagulation by controlling the production of t-PA and PAI-1; 4) Regulation of the vascular permeability. In the states of acute inflammation, the endothelial cell takes on a proinflammatory phenotype and as such becomes chemoattractant, facilitating leukocyte adhesion, activation and migration, becomes prothrombotic and demonstrates enhanced vascular permeability.
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PMID:[The role of endothelial cells in allergic inflammation reactions]. 986 70


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