Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0004135 (ATM)
13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protease nexin-1 (PN-1) is a potent inhibitor of serine proteases, such as thrombin and plasminogen activators, which is secreted into the extracellular space. Since PN-1 is induced following lesion of the sciatic nerve, the effect of substances known to accumulate at the site of injury was examined in primary cultures of Schwann cells. Among the cytokines, growth factors, mitogens, neurotrophins, and neuroactive peptides analyzed, only angiotensin II (Ang II), calcitonin gene-related peptide (CGRP), and vasoactive intestinal peptide (VIP) were found to regulate the expression of PN-1 on Schwann cells. While Ang II and CGRP caused downregulation, VIP acted as a positive modulator of PN-1. Displacement of Ang II binding using the selective ligands losartan and CGP 42112 led to a severalfold increase of PN-1 protein and mRNA over basal levels, indicating that the observed effect was mediated by specific binding sites. Indeed, the presence of AT1 and AT2 angiotensin receptor subtypes was demonstrated in cultured Schwann cells as well as in the rat sciatic nerve. Moreover, the detection of angiotensinogen- and renin-mRNA in these cultures suggested an endogenous production of Ang II. This data identified one of the mechanisms regulating PN-1 synthesis. Altogether our results indicate that neuropeptides can differentially control the proteolytic activity of the microenvironment, providing new aspects of neuron-glia interactions in the intact tissue and following nerve injury.
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PMID:Regulation of protease nexin-1 expression in cultured Schwann cells is mediated by angiotensin II receptors. 782 77

Angiotensin II (ANG II) is known to be a potent growth promoting factor for vascular smooth muscle cells and fibroblasts but little is known about its influence on growth in endothelial cells. We studied the effects of ANG II on endothelial growth and the role of the angiotensin receptor subtypes involved. Proliferation of rat coronary endothelial cells (CEC) and rat vascular smooth muscle cells (VSMC) was determined by [3H]thymidine incorporation, the MTT-test and by directly counting cells in a coulter counter. Angiotensin AT1- and AT2-receptors were demonstrated by binding studies and by the presence of their respective mRNA through reverse transcription polymerase chain reaction (RT-PCR). In contrast to VSMC, which in culture only express the AT1-receptor, CEC express both, AT1- and AT2-receptors simultaneously up to the third passage. Whereas ANG II stimulated growth of quiescent VSMC, an effect abolished by pretreatment with the AT1-receptor antagonist, losartan, ANG II did not induce proliferation in quiescent CEC. However, after pretreatment of quiescent endothelial cells (< passage 4) with the AT2-receptor antagonist, PD 123177, ANG II induced proliferation. This effect was reversed by additional pretreatment with losartan. ANG II significantly inhibited the proliferation of bFGF-stimulated CEC in a dose-dependent manner by maximally 50%. This effect was prevented by PD 123177 while losartan was ineffective. The AT2-receptor agonist, CGP 42112, mimicked the antiproliferative actions of ANG II, confirming the specificity of the effect. Our results show that the growth modulating actions of ANG II depend on the type of angiotensin receptor present on a given cell. In coronary endothelial cells, the antiproliferative actions of the AT2-receptor offset the growth promoting effects mediated by the AT1-receptor.
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PMID:The angiotensin AT2-receptor mediates inhibition of cell proliferation in coronary endothelial cells. 786 Jul 48

In this study we determined which angiotensin receptors may mediate the cardiovascular effects elicited by angiotensin-(1-7) [Ang-(1-7)] in the rostral ventrolateral medulla (RVLM) and caudal pressor area (CPA) of the ventrolateral medulla (VLM) of anesthetized rats. Furthermore the role of endogenous angiotensins in these areas was also investigated. The pressor effect produced by unilateral microinjection of Ang-(1-7) into the RVLM or CPA was not modified by either the AT1 receptor antagonist, DuP 753 or by the AT2 receptor antagonist, CGP 42112A, but was completely blocked by the Ang-(1-7) selective antagonist, A-779. In contrast, the pressor effect produced by microinjection of angiotensin II (Ang II) was completely blocked by DuP 753 but was not changed by CGP 42112A or A-779. Bilateral microinjection of A-779 into the RVLM or CPA produced a significant fall in mean arterial pressure and heart rate. Microinjection of DuP 753 produced a pressor effect comparable to bilateral injection of vehicle. These results indicate that, although Ang II acts in the VLM through an AT1 receptor subtype, the cardiovascular effects produced by microinjection of Ang-(1-7) into the RVLM and CPA are mediated by a specific angiotensin receptor (AT5?). Furthermore, our data provide evidence that endogenous Ang-(1-7) participates at the VLM in the neural control of arterial blood pressure.
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PMID:Evidence that angiotensin-(1-7) plays a role in the central control of blood pressure at the ventro-lateral medulla acting through specific receptors. 788 13

Like RIE-1 cells, two of the IEC series of rat intestinal epithelial cell lines were found to express functional angiotensin receptors. As in RIE-1 cells, treatment of IEC-6 or IEC-18 cells with angiotensin II (AII) activated phosphatidylinositol-4,5-bisphosphate (PIP2) hydrolysis although (in contrast to RIE-1 cells) the magnitude of AII-induced PIP2 hydrolysis was small and not associated with a mitogenic response in either IEC cell line. In terms of their other functional responses to AII (activation of protein kinase C (PKC) and a small elevation of cyclic AMP), IEC-6 cells are otherwise similar to RIE-1 cells whereas IEC-18 cells exhibit some phenotypic differences to the other two cell types. Thus, whereas IEC-6 and RIE-1 cells each express the AT1 subtype of angiotensin receptor, the higher affinity receptors on IEC-18 cells are 'atypical', being insensitive to both AT1- and AT2-specific angiotensin receptor antagonists. Furthermore, in contrast to its effects in IEC-6 and RIE-1 cells, AII neither activates PKC nor modulates cyclic AMP levels in IEC-18 cells. Whereas IEC-18 cells express the myristoylated alanine-rich C-kinase substrate (MARCKS), immunoreactive MARCKS was not detected in IEC-6 or RIE-1 cells.
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PMID:Comparison of the responses of three rat intestinal epithelial cell lines to angiotensin II. 792 Mar 81

The relative binding affinities of non-peptide antagonists, and the sensitivity of 125I-angiotensin II (125I-AII) binding to the reducing agent, dithiothreitol, indicated the presence of AT1 angiotensin receptors on RIE-1 rat intestinal epithelial cells. Consistent with this finding, AT1 angiotensin receptor mRNA was detected in RIE-1 cells using Northern blotting, whereas no mas transcripts (which also encode an angiotensin receptor) were detectable using a RNAse protection assay. At 37 degrees C, 125I-AII rapidly bound to RIE-1 cells and internalised into an acid-inaccessible compartment, which resulted in the depletion of 125I-AII from the binding medium. Following overnight incubation of RIE-1 cells with 125I-AII at 4 degrees C, the majority of bound ligand was also, unexpectedly, found to be inaccessible to subsequent acid elution. After warming these cultures to 37 degrees C, acid-inaccessible 125I-radioactivity rapidly disappeared from the cells, and 125I-labelled degradation products accumulated in the medium. Scatchard analysis of the concentration-dependent binding of 125I-AII solely to the acid-accessible sites on RIE-1 cells revealed little difference to the KD value obtained from total 125I-AII binding (to both acid-accessible and -inaccessible sites), but only approximately 15% of the number of sites.
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PMID:Characterisation of AT1 angiotensin receptors on cultured rat intestinal epithelial (RIE-1) cells. 806 42

1. Angiotensin II (AII) reduces blood flow, modulates vascular remodelling and is a growth factor. Human inflammatory arthritides are characterized by synovial hypoperfusion, hypoxia and proliferation. We aimed to localize and characterize receptors for AII in human synovium. 2. We used quantitative in vitro receptor autoradiography with [125I]-(Sar1, Ile8)AII and [125I]-AII on human synovium from patients with chondromalacia patellae, osteoarthritis and rheumatoid arthritis. 3. [125I]-(Sar1, Ile8)AII and [125I]-AII bound to similar sites on synovial blood vessels, lining cells and stroma. Binding to microvessels (< 100 microns diameter) was more dense than to arteriolar media, and vascular binding was more dense than that to lining cells and stroma. 4. Microvessels and arterioles which displayed angiotensin converting enzyme-like immunoreactivity also displayed specific binding of [125I]-(Sar1, Ile8)AII. 5. Specific binding of [125I]-(Sar1, Ile8)AII to each structure was completely inhibited by 10 microM dithiothreitol and was inhibited by unlabelled ligands with the rank order of potency (Sar1, Ile8)AII > AII > losartan = SKF108566 > PD123319 indicating an AT1 subclass of angiotensin receptor. 6. GTP gamma S (1 microM) abolished specific binding of [125I]-AII and abolished the high affinity component of the binding inhibition curve for AII against [125I]-(Sar1, Ile8)AII, indicating G protein coupling. 7. The distribution of [125I]-(Sar1, Ile8)AII binding sites was similar in all disease groups and no significant differences in binding densities, affinities or specificities were observed between disease groups. 8. Locally generated AII may act on synovial AT1 receptors to modulate synovial perfusion and growth. Specific AT1 receptor antagonists should help elucidate the role of angiotensins in human arthritis.
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PMID:AT1 receptor characteristics of angiotensin analogue binding in human synovium. 807 62

1. In this article we review the physiological actions of the heptapeptide angiotensin-(1-7) [Ang-(1-7)] at the periphery and on central pathways involved in the control of arterial pressure. Peripherally Ang-(1-7) has been shown to present a potent antidiuretic effect on water-loaded rats. Microinjection of pmol amounts of Ang-(1-7) into the dorsomedial or ventrolateral medulla (VLM) of anesthetized rats produces cardiovascular effects comparable to Ang II. In addition, in vitro experiments have shown that Ang-(1-7) has a potent vasopressin and prostaglandin releasing activity and excites neuronal activity in the hypothalamus and medulla. 2. Evidence for the existence of a new angiotensin receptor subtype that mediates the central cardiovascular actions of this active peptide of the renin-angiotensin system (RAS) is also provided. Neither the AT1 receptor antagonist DUP 753 or the AT2 receptor antagonist CGP 42112A blocked the pressor response produced by microinjection of Ang-(1-7) into the rostral VLM. However, the effect of Ang-(1-7) on VLM was completely abolished by the non-specific angiotensin receptor antagonist, Sar1-Thr8-Ang II. 3. The data presented here reinforce the hypothesis of the existence of complex site-specific interactions between multiple angiotensins and multiple receptors in the mediation of important central and peripheral effects of the RAS.
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PMID:Central and peripheral actions of angiotensin-(1-7). 808 84

Rats were given intracerebroventricular injections of either angiotensin II (ANG II) or the cholinomimetic carbachol. Some rats received cotreatment with ANG II antagonists selective for either angiotensin receptor AT1 (losartan) or AT2 (PD-123319, CGP-42112A). One hour later, the rats were killed and the brains processed for immunocytochemical detection of Fos-like immunoreactivity (FLI). ANG II treatment induced strong FLI in the anterior subfornical organ (SFO), median preoptic nucleus (MnPO), organum vasculosum laminae terminalis (OVLT), and supraoptic and paraventricular hypothalamic nuclei (SON, PVH). The AT1 antagonist abolished FLI in all regions normally stimulated by ANG II. The AT2 antagonist PD-123319 reduced FLI in SON and PVH, but CGP-42112A was less effective. Carbachol induced strong FLI in SON, PVH, and MnPO and only moderate FLI in SFO and OVLT. The AT1 antagonist prevented carbachol-induced FLI in the MnPO only. The distributions of FLI are compared between these central dipsogens and with that previously reported after peripheral infusion of ANG II, and their implications for mapping central thirst pathways are discussed.
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PMID:Comparison of fos-like immunoreactivity induced in rat brain by central injection of angiotensin II and carbachol. 809 25

Angiotensin(1-7) had a compound effect on blood pressure of pithed Sprague-Dawley rats. The initial phase of the response consisted of an increase in MAP of short duration and independent of injected dose, followed by a decline of arterial pressure to values below baseline. Both the magnitude (range: -4 +/- 1 to -13 +/- 1 mmHg) and the duration (range: 83 +/- 13 to 255 +/- 17 s) of the depressor response correlated with the dose of peptide. Indomethacin (5 mg/kg) eliminated the depressor component. Only [Sar1,Thr8]Ang II inhibited the effect of Ang(1-7) completely. We conclude that angiotensin(1-7) possesses myotonic actions that are in part related to release of vasodilator prostaglandins through an angiotensin receptor other than AT1 or AT2.
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PMID:Cardiovascular actions of angiotensin(1-7). 823 10

We report the cloning of a gene, intronless in its coding region, which we have named APJ. This gene was cloned using the polymerase chain reaction (PCR), with a set of primers designed on the basis of the conservation that members of G protein-coupled receptors (GPCR) have in their transmembrane (TM) regions. The putative receptor protein, APJ, shares closest identity to the angiotensin receptor (AT1) ranging from 40 to 50% in the hydrophobic TM regions of these receptors. The transcripts for this gene were detected in many regions of the brain. PCR analysis of somatic cell lines found APJ-related sequences to be only present on chromosome 11, and high-resolution mapping by fluorescence in situ hybridization (FISH) sublocalized APJ on band q12.
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PMID:A human gene that shows identity with the gene encoding the angiotensin receptor is located on chromosome 11. 829 32


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