Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In healthy subjects, intravenous infusion of the selective V2-vasopressin receptor agonist 1-desamino-8-D-arginine vasopressin (DDAVP, 400 ng/kg in 10 min) causes a marked increase in heart rate with a slight decrease in diastolic blood pressure. These haemodynamic responses are associated with increments in the plasma levels of renin, noradrenaline (NA), clotting factor VIII (FVIII:C), von Willebrand factor (vWF:ag), and tissue-type plasminogen activator (t-PA), and a fall in the plasma level of plasminogen activator inhibitor (PAI). None of these changes was observed in 3 patients with congenital nephrogenic diabetes insipidus (NDI), who had a genetic defect of the V2-receptor. Plasma AVP levels in these patients were normal or slightly elevated, which makes it unlikely that the lack of DDAVP responsiveness was caused by down-regulation of vasopressin V1-receptors. In one NDI patient, arginine vasopressin (AVP) was given in incremental doses (62.5-4000 pg/kg/min). The heart rate and blood pressure responses to AVP were normal, indicating the absence of a V1-receptor defect. The responses of vWF:ag and t-PA to venous occlusion in the patients with NDI were similar to those in 5 healthy volunteers, which indicates that in NDI the endothelial release of both vWF:ag and t-PA is normal. We conclude that DDAVP causes its effects on heart rate and blood pressure, and on the plasma levels of renin, noradrenaline, FVIII:C, vWF:ag, and t-PA through V2-receptor stimulation.
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PMID:1-Desamino-8-D-arginine vasopressin (DDAVP) in patients with congenital nephrogenic diabetes insipidus. 823 94

Plasma levels of tissue type plasminogen activator (tPA), plasminogen activator inhibitor (PAI), fibrinogen (Fg), thromboxane B2 (TXB2), 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), renin activity (PRA) and angiotensin II (ANGII) were assayed in 18 patients with coronary heart disease and 11 healthy subjects before and after submaximal treadmill exercise test according to "Bruce programme". All patients showed significant (> or = 50%) stenosis of at least one branch of the coronary arteries in coronary angiography and normal levels of serum trinitroglycerin. Drugs of dipyridamole, heparin, warfarin and aspirin were not administered to the patients two weeks before the test. The results were as follows: (1) Plasma PAI activity and Fg levels in 12 patients with positive test were remarkablly higher than in the remaining 6 subjects with negative test in the CHD group and in the control before and after exercise. Plasma tPA antigen changed in a reverse way. (2) Plasma levels of TXB2, PRA and ANGII in the positive test subgroup of CHD were higher than in the negative test subgroup and in the control after exercise, but differences of the parameters among the three groups were insignificant before exercise. The study suggests that defectiveness of fibrinolytic system in CHD patients was shown mainly as disorder of tPA-PAI equilibrium and that decreased fibrinolytic activity and increased PAI in exercise-induced myocardial ischemia have relations with activation of platelets and renin-angiotensin system.
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PMID:[Clinical significance of fibrinolytic system defectiveness in exercise induced myocardial ischemia and its mechanism]. 856 12

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

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

Overproduction of transforming growth factor-beta clearly underlies tissue fibrosis in numerous experimental and human diseases. Transforming growth factor-beta's powerful fibrogenic action results from simultaneous stimulation of matrix protein synthesis, inhibition of matrix degradation, and enhanced integrin expression that facilitates matrix assembly. In animals, overexpression of transforming growth factor-beta by intravenous injection, transient gene transfer, or transgene insertion has shown that the kidney is highly susceptible to rapid fibrosis. The same seems true in human disease, where excessive transforming growth factor-beta has been demonstrated in glomerulonephritis, diabetic nephropathy, and hypertensive glomerular injury. A possible explanation for the kidney's particular susceptibility to fibrosis may be the recent discovery of biologically complex interactions between the renin-angiotensin system and transforming growth factor-beta. Alterations in glomerular hemodynamics can activate both the renin-angiotensin system and transforming growth factor-beta. Components of the renin-angiotensin system act to further stimulate production of transforming growth factor-beta and plasminogen activator inhibitor leading to rapid matrix accumulation. In volume depletion, transforming growth factor-beta is released from juxtaglomerular cells and may act synergistically with angiotensin II to accentuate vasoconstriction and acute renal failure. Interaction of the renin-angiotensin system and transforming growth factor-beta has important clinical implications. The protective effect of inhibition of the renin-angiotensin system in experimental and human kidney diseases correlates closely with the suppression of transforming growth factor-beta production. This suggests that transforming growth factor-beta, in addition to blood pressure, should be a therapeutic target. Higher doses or different combinations of drugs that block the renin-angiotensin system or entirely new drug strategies may be needed to achieve a greater antifibrotic effect.
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PMID:Interactions of transforming growth factor-beta and angiotensin II in renal fibrosis. 945

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

Circulating levels of angiotensin-converting enzyme (ACE) in humans are linked with an insertion (I)/deletion (D) polymorphism in the ACE gene: DD genotype bearers have higher levels of ACE than either ID or II genotype bearers. Recent studies have suggested that the ACE DD genotype may be associated with a higher risk of coronary artery disease. The aim of this paper is to review studies on the influence of I/D polymorphism on coronary restenosis, coronary vasomotion and coronary thrombosis. The renin angiotensin system has been implicated in the pathogenesis of neointimal hyperplasia in experimental models. In humans, I/D polymorphism is not associated with restenosis after balloon angioplasty but is strongly associated with restenosis after coronary stent implantation. This may be explained by the fact that the contribution of neointimal hyperplasia to restenosis is much more important after coronary stent implantation than after balloon angioplasty. The renin angiotensin system may participate in the regulation of coronary vasomotion. An association between I/D polymorphism and coronary artery spasm has been reported. An increased production of plasminogen activator inhibitor-I and an increase in platelet aggregability may explain the higher risk of coronary thrombosis in subjects with high levels of ACE. The ACE I/D genotype has been associated with a lower incidence of a patent infarct-related artery after myocardial infarction and with a higher risk of total occlusion of the dilated site 6 months after successful balloon angioplasty. These studies suggest that the influence of the I/D polymorphism on coronary artery disease may be multifactorial. Possible mechanisms include interactions with neointimal formation, coronary artery spasm and coronary thrombosis.
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PMID:Association between the ACE genotype and coronary artery disease. Insights from studies on restenosis, vasomotion and thrombosis. 979 37

We investigated whether plasma levels of the plasminogen activator inhibitor type 1 antigen (PAI-1:Ag) are genetically determined in monozygotic (MZ) and dizygotic (DZ) twins. Twenty-five pairs of healthy twins underwent measurements of PAI-1:Ag and other variables, including body mass index, mean blood pressure, plasma renin activity, insulin, and glucose. To ascertain the zygosity of twins, highly discriminating micro- and minisatellite systems with variable numbers of tandem repeats were analyzed by PCR amplification followed by polyacrylamide gel electrophoresis. Subjects were also genotyped for the 4G/5G polymorphism by PCR. Estimates of genetic variance and heritability were obtained for PAI-1:Ag, and for body mass index, mean blood pressure, plasma renin activity, glucose, and insulin by jointly examining data in a path analysis with TWINAN90. Results showed that 12 pairs of twins were MZ and 13 were DZ. All tests of genetic variance [within pair (WP): F=6.24, P=0.002; among component (AC): F=2.62, P=0.04; average absolute difference t test=3. 00, P=0.004] showed significant genetic variance of PAI-1:Ag, but not of the other variables. Three tests of heritability (WP=0.837, P=0.002; AC=1.791, P<0.05; intraclass correlation: 1.180, P=0.001) consistently showed significant PAI-1:Ag heritability. Additive genetic influences (A), dominance genetic effect (D), and random environmental influences (E) accounted for 0.714, 0.154, and 0.132 of PAI-1:Ag variance, respectively. No effect of different 4G/5G genotypes was found. Thus, these results show significant genetic variance and heritability of PAI-1:Ag and suggest that A is more important than both D and E in determining PAI-1:Ag variance.
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PMID:Determinants of plasma levels of plasminogen activator inhibitor-1 : A study of normotensive twins. 997 13

This study aimed to identify the intracellular signaling pathway in angiotensin II (Ang II)-induced upregulation of plasminogen activator inhibitor type 1 (PAI-1) mRNA expression in cultured rat glomerular mesangial cells, and to examine the interaction between Ang II and TGF-beta signaling. Ang II-induced upregulation of PAI-1 mRNA expression was prevented by a protein kinase C (PKC) inhibitor, bisindorylmaleimide I. While phorbol 12-myristate 13-acetate (PMA) upregulated the PAI-1 mRNA expression, a calcium ionophore, ionomycin, had little effect. Mesangial cells pretreated with PMA for 24 h to downregulate PKC demonstrated attenuated response to Ang II. A protein tyrosine kinase inhibitor, genistein, completely blocked both Ang II- and PMA-induced PAI-1 mRNA expression. Transforming growth factor-beta1 (TGF-beta1) alone induced the expression, and in the presence of Ang II, TGF-beta1 superinduced PAI-1 mRNA expression to a higher extent. Both bisindorylmaleimide I and genistein suppressed the Ang II plus TGF-beta1-induced PAI-1 mRNA upregulation to the basal level, while downregulation of PKC attenuated the synergistic upregulation of PAI-1 mRNA expression to the level comparable to TGF-beta1 alone. These data suggest that, in rat mesangial cells, (1) PKC and protein tyrosine kinase(s) are involved in the Ang II signaling cascade, (2) protein tyrosine kinase(s) works downstream from PKC in the cascade, and (3) there is an interaction between the Ang II and TGF-beta signal pathways downstream from PKC. In in vivo settings, local activation of renin-angiotensin and TGF-beta systems in the glomeruli may synergistically augment PAI-1 expression, promote mesangial matrix accumulation and progression of glomerular injury.
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PMID:Association of TGF-beta signaling in angiotensin II-induced PAI-1 mRNA upregulation in mesangial cells: role of PKC. 1020 1


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