UNIPROT:P00750 - FACTA Search

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)

A highly active angiotensin-producing enzyme (enzyme II) was obtained from dog serum by acid treatment and fractionation to remove angiotensinase and converting enzyme, separate an inhibitor, and convert an inactive precursor (proenzyme II) to enzyme II. Proenzyme II was found to be converted to enzyme II by an endogenous activating enzyme identified as plasmin. Conversion was also caused by the interaction of bacterial streptokinase with human proactivator, by trypsin, and by an activator formed from liver tissue extract and dog serum. Neither plasma kallikrein nor the labile, human extrinsic tissue-type plasminogen activator induced activation. The inhibitor, which normally blocks the activation of proenzyme II, was unusually stable against high temperatures and extremes of pH, and it was not identical to any of the six known protease inhibitors of serum. Enzyme II was not identical to other angiotensin-producing enzymes such as enzyme I, renin, cathepsin D, pepsin, plasmin, tonin, or cathepsin G. Enzyme II reacted maximally at pH 4.7 and produced up to 2250 ng of angiotensin I/ml serum/hr from the substrate of dog serum (i.e., amounts 3200-fold higher than that produced by endogenous renin of normal dog serum). Since at pH 7.2, angiotensin I formation is still about 30 times higher than that of renin, enzyme II may be physiologically active under some conditions.
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PMID:Angiotensin-producing serum enzyme II. Formation by inhibitor removal and proenzyme activation. 390 15

The concept of classical endocrine control of ovarian function has now been extended to a more complex regulator system, including paracrine and autocrine modulating mechanisms. Among many factors, locally produced intraovarian insulin-like growth factors (IGFs) and the binding proteins (IGFBPs) and renin-angiotensin system (RAS) have been shown to play an important role in the control of folliculogenesis and ovulation. Growth hormone (GH) amplified gonadotropin actions in the process of follicular development and ovulation, at least in part, stimulating ovarian IGF-I production. IGF-I as well as IGFBPs were produced by ovarian granulosa cells. IGF-I acted synergistically with gonadotropins in the stimulation of a variety of granulosa cell functions, including estradiol (E2) and progesterone production and plasminogen activator (PA) activity. Furthermore, rabbit ovarian cells and rat granulosa cells possessed specific IGF type I receptors. The biological effects of IGF-I, including intrafollicular PA activities and ovarian steroidogenesis, were modulated by a family of IGFBPs in a complex manner. In the ovary IGFBP-3 appeared to neutralize the actions of gonadotropin and IGF-I, probably via its ability to sequester IGF-I, in the process of follicular growth, oocyte maturation, and ovulation. A functional local RAS is also known to exist in the ovary. Angiotensin II (Ang II) at 2-h intervals induced oocyte maturation, ovulation, and the production of E2 and prostaglandins (PGs) in the in vitro perfused rabbit ovaries in the absence of gonadotropin. In addition, the intrafollicular Ang II content and renin-like activity were enhanced during the ovulatory process by exposure to hCG, and the concomitant addition of saralasin inhibited hCG-induced ovulation in a dose-dependent manner. Captopril, an inhibitor of angiotensin converting enzyme, significantly inhibited the resumption of meiosis in the ovulated ova and follicular oocytes stimulated by hCG. Autoradiographic study revealed that AT2 receptors were predominantly located in granulosa cells, whereas AT1 receptors were more concentrated in the stroma and the thecal layers. Ang II-stimulated production of E2 and PGs and ovulation were significantly blocked by PD123319, a selective nonpeptide antagonist for AT2 receptors. The increase in ovarian IGF-I synthesis by exposure to hCG or GH induced the stimulation of intrafollicular PA activities. IGFBP-3 blocked the stimulatory effects of gonadotropin in the ovulatory process by neutralizing endogenously produced IGF-I, resulting in reduced intrafollicular PA activities. The increase in intrafollicular PA activities significantly stimulated the generation of Ang II in the preovulatory follicles by an activation of prorenin to renin and/or by the direct cleavage of angiotensinogen.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Regulatory system and physiological significance of local factors in the ovary during follicular development and maturation]. 759 85

Plasminogen activator-inhibitor C-1 (PAI-1) plays a critical role in the regulation of fibrinolysis, serving as the primary inhibitor of tissue-type plasminogen activator. Elevated levels of PAI-1 are a risk factor for recurrent myocardial infarction, and locally increased PAI-1 expression has been described in atherosclerotic human arteries. Recent studies have shown that the administration of angiotensin converting enzyme inhibitors reduces the risk of recurrent myocardial infarction in selected patients. Since angiotensin II (Ang II) has been reported to induce PAI-1 production in cultured astrocytes, we have hypothesized that one mechanism that may contribute to the beneficial effect of angiotensin converting enzyme inhibitors is an effect on fibrinolytic balance. In the present study, we examined the interaction of Ang II with cultured bovine aortic endothelial cells (BAECs) and the effects of this peptide on the production of PAI-1. 125I-Ang II was found to bind to BAECs in a saturable and specific manner, with an apparent Kd of 1.4 nM and Bmax of 74 fmol per mg of protein. Exposure of BAECs to Ang II induced dose-dependent increases in PAI-1 antigen in the media and in PAI-1 mRNA levels. Induction of PAI-1 mRNA expression by Ang II was not inhibited by pretreating BAECs with either Dup 753 or [Sar1, Ile8]-Ang II, agents that are known to compete effectively for binding to the two major angiotensin receptor subtypes. These data indicate that Ang II regulates the expression of PAI-1 in cultured endothelial cells and that this response is mediated via a pharmacologically distinct form of the angiotensin receptor.
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PMID:Angiotensin II regulates the expression of plasminogen activator inhibitor-1 in cultured endothelial cells. A potential link between the renin-angiotensin system and thrombosis. 788 1

Neuronal cells in primary culture from the hypothalamus-brain stem areas of normotensive [Wistar-Kyoto (WKY)] and spontaneously hypertensive (SH) rat brains have been used in the present study to investigate an interaction between the brain renin-angiotensin II system and the plasminogen activator system. This is an attempt to further our understanding of the role of brain Ang II in the control of neuronal development and differentiation through its regulation of the extracellular matrix. Ang II caused a 10-fold stimulation of plasminogen activator inhibitor-1 (PAI-1) messenger RNA (mRNA) in WKY rat brain neuronal cultures. The stimulation was mediated by the AT1 receptor subtype and was accompanied by an increase in PAI-1 gene transcription and the synthesis of cellular PAI-1 protein. The stimulation involved activation of protein kinase C, and alterations in the intracellular Ca2+ pool caused a significant inhibition of Ang II stimulation of PAI mRNA. Ang II stimulation of PAI-1 mRNA succeeded its action on c-fos mRNA and was attenuated by c-fos antisense oligonucleotide. Although PAI-1 gene expression was also stimulated by Ang II in neuronal cultures of SH rat brain, two differences between WKY and SH rat brain neurons were observed: 1) the level of Ang II stimulation in SH rat neurons was 50% of that in WKY rat neurons; and 2) Ang II stimulation of c-fos was 2.4-fold higher in SH neurons than in WKY neurons, but c-fos antisense oligonucleotide did not attenuate the stimulatory action of Ang II on PAI-1 mRNA in SH neurons. These observations suggest that the changes in the Ang II-mediated signaling pathways and/or the regulatory region(s) of the PAI-1 gene may contribute to the differential actions of Ang II in WKY and SH rat brain neurons.
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PMID:Angiotensin II regulation of plasminogen activator inhibitor-1 gene expression in neurons of normotensive and spontaneously hypertensive rat brains. 864 Dec 4

The interactions between insulin-like growth factor-I (IGF-I) and the renin-angiotensin system (RAS) in follicular growth and ovulation were studied with the use of an isolated perfused rabbit ovary preparation. Ovulation failed to occur in either control ovaries or the experimental ovaries perfused with IGF-I in a concentration of 1, 10, or 100 ng/ml in the absence of gonadotropin. Exposure to IGF-I stimulated the secretion rate of angiotensin II-like immunoreactivity (Ang II-IR) in perfused rabbit ovaries in a dose-dependent manner. The percent increase in follicle diameter in ovaries perfused with IGF-I for 12 h was significantly correlated with the secretion rate of Ang II-IR at 12 h after exposure to IGF-I. The addition of IGFBP-3 to the perfusate did not induce ovulation in the absence of gonadotropin, but exposure to IGFBP-3 inhibited hCG-induced ovulation in a dose-dependent manner. In addition, IGFBP-3 significantly reduced the ovarian secretion rate of Ang II-IR and prostaglandins stimulated by hCG administration. Intrafollicular plasminogen activator (PA) activity significantly increased within 4 h after exposure to 100 ng/ml of IGF-I, compared with that in control ovaries perfused with medium alone. The concomitant addition of IGFBP-3 to the perfusate significantly reduced the IGF-I-stimulated PA activity in the preovulatory follicles at 4, 6, and 8 h after exposure to IGF-I. However, IGFBP-3 alone affected neither the ovarian secretion rate of Ang II-IR nor intrafollicular PA activity. Exposure to streptokinase, an exogenous PA, in vitro stimulated both follicular growth and the intrafollicular Ang II-IR content. In conclusion, IGF-I enhances both ovarian Ang II production and follicular development by stimulating intrafollicular PA activity.
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PMID:Interactions between insulin-like growth factor-I (IGF-I) and the renin-angiotensin system in follicular growth and ovulation. 875 39

We examined the potential of in vivo linkage of plasminogen activator inhibitor-1 (PAI-1) and angiotensin II (Ang II) in the setting of endothelial injury and sclerosis following radiation injury in the rat. PAI-1 is a major physiological inhibitor of the plasminogen activator (PA)/plasmin system, a key regulator of fibrinolysis and extracellular matrix (ECM) turnover. PAI-1 mRNA expression in the kidney was markedly increased (9-fold) at 12 weeks after irradiation (P < 1.001 vs. normal control). In situ hybridization revealed significant association of PAI-1 expression with sites of glomerular injury (signal intensity in injured vs. intact glomeruli, P < 0.001). Angiotensin converting enzyme inhibitors (ACEI, captopril or enalapril) or angiotensin II receptor antagonist (AIIRA, L158,809) markedly reduced glomerular lesions (thrombosis, mesangiolysis, and sclerosis; sclerosis index, 0 to 4+ scale, 0.49 +/- 0.20 in untreated vs. 0.05 +/- 0.02, 0.02 +/- 0.01, 0.04 +/- 0.02 in captopril, enalapril and AIIRA, respectively, all P < 0.01 vs untreated). Further, ACEI and AIIRA markedly attenuated increased PAI-1 mRNA expression in the irradiated kidney (36, 19 and 20% expression, respectively, for captopril, enalapril and AIIRA, compared to untreated irradiated kidney, P < 0.05, < 0.01, < 0.01). This effect was selective in that neither tissue-type nor urokinase-type PA mRNA expression was affected by these interventions. Thus, we speculate that inhibition of the renin-angiotensin system may ameliorate injury following radiation by accelerating fibrinolysis and ECM degradation, at least in part, via suppression of PAI-1 expression. In summary, inhibition of Ang II, in addition to its known effects on vascular sclerosis, may also by its novel effect to inhibit PAI-1, lessen fibrosis following endothelial/thrombotic injury.
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PMID:Modulation of plasminogen activator inhibitor-1 in vivo: a new mechanism for the anti-fibrotic effect of renin-angiotensin inhibition. 899 30

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

Angiotensin converting inhibitors (ACEI) not only decrease angiotensin II (Ang II) but also potentiate the effects of bradykinin. Bradykinin is a potent stimulus to tissue type plasminogen activator (t-PA) secretion in animal models. In this study, we tested the hypothesis that bradykinin increase t-PA levels in humans. Bradykinin was infused in seventeen hypertensive patients randomized to treatment with the ACEIs captopril and quinapril or with placebo. Bradykinin caused a significant decrease in mean arterial pressure (MAP) (p = 0.014) and increase in pulse (p < 0.001). ACEI significantly potentiated the hemodynamic effect of bradykinin (p < 0.05). Although baseline t-PA antigen levels were similar in the ACEI-treated (6.85 +/- 0.85 ng/ml) and placebo-treated (7.85 +/- 0.68 ng/ml) subjects, bradykinin caused a significant (p < 0.01) increase in t-PA antigen levels (to 19.3 +/- 8.2) only in the ACEI-treated patients. This increase in t-PA was independent of activation of the sympathetic nervous system. Bradykinin had no effect on PAI-1 antigen levels. These in vivo data suggest that infusion of bradykinin results in an increase in circulating t-PA levels without an effect on PAI-1.
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PMID:Selective stimulation of tissue-type plasminogen activator (t-PA) in vivo by infusion of bradykinin. 906 5

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

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

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