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Query: UNIPROT:P06889 (Mol)
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Angiotensin II (AII) binding sites were characterized in human myometrium membrane preparations. The sites were saturable and of high affinity (Kd of 0.09 nM and Bmax of about 200 fmol/mg of protein). PD 123319 completely inhibited 125I-AII binding, with an IC50 of 30 nM, whereas L-158,809 (1 microM) had no significant effect on 125I-AII binding. These results indicate that human myometrium contains almost exclusively the AT2 receptor subtype. Association and dissociation studies performed with 125I-AII on human myometrium membranes revealed that AII had a very high affinity for AT2 receptors, with a Kd of 0.01 nM (association rate constant K1 = 1.056 x 10(12) mol-1 min-1; dissociation rate constant K2 = 0.003 min-1). The photoactivable AII analogue [Sar1, Val5, D-Phe8(N3)]AII displayed a high affinity for AT2 receptors (IC50 of 0.18 nM), but its radioiodinated form showed poor efficiency in photoaffinity labeling experiments. A newly synthesized photoactivatable analogue of AII, [Sar1, p-benzoyl-Phe8]AII, (AII-Bpa), also displayed a high affinity for AT2 receptors of human myometrium (IC50 of 0.3 nM). Photoaffinity labeling experiments were performed with 125I-AII-Bpa, and a high yield (70%) of covalent incorporation to human myometrium membranes was obtained upon photolysis. Covalently labeled receptors were solubilized, denatured, and subjected to polyacrylamide gel electrophoresis. Autoradiography of the polyacrylamide gel revealed a single band, of 68 kDa, and the labeling of this band was completely abolished in the presence of 1 microM PD 123319, indicating selective labeling of the AT2 receptor subtype. These results demonstrate that AII-Bpa is a very efficient tool for selective photoaffinity labeling of the AT2 receptor.
Mol Pharmacol 1993 May
PMID:Photoaffinity labeling of subtype 2 angiotensin receptor of human myometrium. 850 25

Angiotensin II (Ang II) has been implicated in the development of cardiac hypertrophy and myocardial fibrosis. While recent in vivo and in vitro studies performed in cultured cardiac myocytes and fibroblasts support this role for Ang II, the mechanisms of Ang II action at the cellular level remain unclear. In the present study, we postulated that Ang II action in adult cardiac fibroblasts may stimulate the autocrine production and release of transforming growth factor-beta 1 (TGF-beta 1), a known regulator of cardiac fibroblast and myocyte function. We examined the ability of Ang II to regulate the gene expression, biological activity, and protein production of TGF-beta 1 in cultured adult rat cardiac fibroblasts. Treatment of fibroblast cultures with Ang II (10(-9) M) induced a two-fold increase in TGF-beta 1 mRNA levels within 4 h that was sustained through 24 h (P < 0.01). TGF-beta 1-like activity in Ang II-treated cultures was significantly increased compared with control as measured by bioassay (P < 0.001). Specificity for TGF-beta 1-like activity was confirmed through its neutralization with a TGF-beta 1 specific antibody (100 micrograms/ml). Total concentration of TGF-beta 1 (latent plus active forms) in conditioned media from Ang II-treated cardiac fibroblasts was also found to be greater than control (P < 0.01). These findings suggest that the effects of Ang II in the adult myocardium may be mediated in part by autocrine/paracrine mechanisms, including the production and release of TGF-beta 1 by cardiac fibroblasts.
J Mol Cell Cardiol 1995 Oct
PMID:Angiotensin II stimulates the autocrine production of transforming growth factor-beta 1 in adult rat cardiac fibroblasts. 857 49

Angiotensin II acts as a cardiac growth factor, and causes both inotropic and chronotropic changes within the heart. In the present study, we used an in oculo model system to examine the effects of sympathetic innervation on the density of cardiac angiotensin II receptors. Quantitative autoradiography was used to determine the density of angiotensin II receptors in embryonic rat hearts grafted into either sympathetically innervated or sympathetically denervated eye chambers of adult host rats. The density of specific binding to angiotensin II receptors was nearly three-fold higher in sympathetically non-innervated compared to sympathetically innervated heart grafts (30.8 +/- 4.2 v 11.5 +/- 3.2 fmol/mg protein). Specific binding to angiotensin II receptors in heart grafts was displaced by addition of the AT1 receptor antagonist losartan, but not by addition of the AT2 receptor competitor PD 123177. Thus, only AT1 receptors were present in sympathetically innervated and sympathetically non-innervated embryonic rat hearts grafted in oculo. We conclude that changes in sympathetic innervation caused changes in the density of cardiac angiotensin II receptors in the present study. Our results may have implications for growth and function not only during cardiac development, but also during cardiac disease.
J Mol Cell Cardiol 1995 Nov
PMID:Sympathetic innervation modulates the expression of angiotensin II receptors in embryonic rat heart grafted in oculo. 859 95

G-protein coupled Angiotensin II receptors (AT1A), mediate cellular responses through multiple signal transduction pathways. In AT1A receptor-transfected CHO-K1 cells (T3CHO/AT1A), angiotensin II (AII) stimulated a dose-dependent EC50 = 3.3 nM) increase in cAMP accumulation, which was inhibited by the selective AT1, nonpeptide receptor antagonist EXP3174. Activation of protein kinase C, or increasing intracellular Ca2+ with ATP, the calcium ionophore A23187 or ionomycin failed to stimulate cAMP accumulation. Thus, AII-induced cAMP accumulation was not secondary to activation of a protein kinase C- or ca2+/calmodulin-dependent pathway. Since cAMP has an established role in cellular growth responses, we investigated the effect of the AII-mediated increase in cAMP on cell number and [3H]thymidine incorporation in T3CHOA/AT1A cells. AII (1 microM) significantly inhibited cell number (51% at 96 h) and [3H]thymidine incorporation of 68% at 24 h) compared to vehicle controls. These effects were blocked by EXP3174, confirming that these responses were mediated through the AT1 receptor. Forskolin (10 microM) and the cAMP analog dibutyryl-cAMP (1 mM) also inhibited [3H]thymidine incorporation by 55 and 25% respectively. We extended our investigation on the effect of AII-stimulated increases in cAMP, to determine the role for established growth related signaling events, i.e., mitogen-activated protein kinase activity an tyrosine phosphorylation of cellular proteins. AII-stimulated mitogen-activated protein kinase activity and phosphorylation of the 42 and 44 kD forms. These events were unaffected by forskolin stimulated increases in cAMP, thus the AII-stimulated mitogen-activated protein kinase activity was independent of cAMP in these cells. AII also stimulated tyrosine phosphorylation of a number of cellular proteins in T3CHO/AT1A cells, in particular at 127 kD protein. The phosphorylation of the 127 kD protein was transient, reaching a maximum at 1 min, and returning to basal levels within 10 min. The dephosphorylation of this protein was blocked by a selective inhibitor of cAMP dependent protein kinase A, H89-dihydrochloride and preexposure to forskolin prevented the AII-induced transient tyrosine phosphorylation of the 127 kD protein. These data suggest that cAMP, and therefore protein kinase A can contribute to AII-mediated growth inhibition by stimulating the dephosphorylation of substrates that are tyrosine phosphorylated in response to AII.
Mol Cell Biochem 1995 Nov 08
PMID:A role for cAMP in angiotensin II mediated inhibition of cell growth in AT1A receptor-transfected CHO-K1 cells. 860 15

1. Angiotensin II is a well-known vasopressive octapeptide that is the principal end-product of the renin-angiotensin system. In addition to its tonic effect on vascular smooth muscle cells, it also stimulates aldosterone secretion from the adrenals and promotes sodium reabsorption through renal tubular cells. 2. These physiological functions have been appreciated for some time, but as details of the molecular and cell biology of the angiotensin response mechanism become understood, it is increasingly apparent that the hormone has a much broader repertoire. Its functional variability is made possible by (i) different enzymatic routes for its generation, (ii) different receptors distributed in different tissues, (iii) different mechanisms for receptor regulation, and (iv) different signal transduction pathways. 3. This insight is the direct consequence of advances in pharmacology that led first to inhibitors of angiotensin converting enzyme and later to angiotensin II receptor antagonists. This review looks at the current status of angiotensin biochemistry and physiology and provides a basis for anticipation of future developments.
Cell Mol Neurobiol 1995 Dec
PMID:Angiotensin II: biosynthesis, molecular recognition, and signal transduction. 871 34

Angiotensin II has been demonstrated to be involved in the regulation of cellular growth of several tissues in response to developmental, physiological, and pathophysiological processes. Angiotensin II has been implicated in the developmental growth of the left ventricle in the neonate and remodeling of the heart following chronic hypertension and myocardial infarction. The inhibition of DNA synthesis and collagen deposition in myocardial interstitium following myocardial infarction by angiotensin converting enzyme inhibitor, suggests that angiotensin II mediates interstitial and perivascular fibrobrosis by preventing fibroblast proliferation. In the past, little attention was focused on the identity and functional roles of cardiac fibroblasts. Recent in vitro studies utilizing cultured cardiac fibroblasts demonstrate that angiotensin II, acting via the AT1 receptor, initiates intracellular signalling pathways in common with those of peptide growth factors. Below, we describe growth-related aspects of cardiac fibroblasts with respect to angiotensin II receptors, conventional and novel signal transduction systems, secretion of extracellular matrix proteins and growth factors, and localization of renin-angiotensin system components.
Mol Cell Biochem
PMID:Angiotensin II signalling pathways in cardiac fibroblasts: conventional versus novel mechanisms in mediating cardiac growth and function. 873 24

Angiotensin II (Ang) injected intracerebroventricularly stimulates neurohypophyseal vasopressin (AVP) release into the peripheral circulation. As we have shown previously, central actions of Ang II in the rat forebrain are mediated by the AT1A receptor subtype. In the present paper, we attempted to clarify the cellular localization of the AT1A receptor mRNA in the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei, in order to reappraise the conflicting data on the nature of the angiotensin II receptor involved in Ang induced vasopressin release. For this purpose, double in situ hybridization was performed using a radioactive AT1A receptor riboprobe and a digoxygenin labeled AVP oligoprobe, and immunohistochemical localization of the glial marker glial fibrillary acidic protein (GFAP) on the same brain slice. The results show neuronal expression of AT1A receptor mRNA mainly in dorsal and medial parvocellular parts of the PVN, its localization in some magnocellular PVN neurons and the absence of its expression in AVP producing neurons either in the PVN or in the SON. Thus, while indirect evidence indicates the involvement of the AT1A receptor subtype in the regulation of CRH and oxytocin release, the stimulation of vasopressinergic neurons is likely due to indirect mechanisms, or to a yet unknown type of angiotensin receptor.
Brain Res Mol Brain Res 1995 Dec 01
PMID:Comparative expression of vasopressin and angiotensin type-1 receptor mRNA in rat hypothalamic nuclei: a double in situ hybridization study. 875 Aug 69

The synthesis regulation of secretogranin II was investigated in bovine chromaffin cells by treatment with various first messengers. Nicotine and prostaglandin E2 elevated secretogranin II mRNA and protein up to three-fold. Angiotensin II, atrial natriuretic peptide, apomorphine, bradykinin and clonidine on the other hand had no effect. The prostaglandin E induced elevation of secretogranin II mRNA was transduced via the calcium/calmodulin pathway but not via the protein kinase A or C pathways as shown by using specific inhibitors. Exposure of chromaffin cells to drugs specifically activating second messenger pathways both elevated and decreased secretogranin II mRNA. The calcium channel agonist Bay K, forskolin and phorbol esters increased secretogranin II mRNA whereas 8-Br-cGMP repressed the secretogranin II message. Thus, although secretogranin II expression can be altered by all major second messenger transduction systems, regulation of secretogranin II in vivo occurs mainly via the calcium/calmodulin pathway. Chromogranin A and B mRNA were not changed by any of the first messengers investigated indicating a differential synthesis regulation of components co-stored in bovine chromaffin granules.
Brain Res Mol Brain Res 1996 Jun
PMID:Nicotine and prostaglandin E induce secretogranin II levels in bovine chromaffin cells. 879 14

Angiotensin II has two major receptor subtypes, designated AT1 and AT2. Both have been detected in the heart of several species, but most of the known functions of angiotensin II seem to be mediated through the AT1 receptor. The major objective of this study was to specify the cell type on which the AT2 receptor is located in the atrium of human heart. Right atrial biopsies from patients with coronary artery disease were tested in membrane binding assays and found to contain high levels of angiotensin II receptor (820 +/- 175 fmol/mg), 82 +/- 2% of which was of the AT2 subtype. Cryostat sections of these biopsies were incubated with 125I-[Sar1,Ile8] angiotensin II in the presence of selective concentrations of the cold ligands losartan and CGP 42112A to detect the subtypes using microscopic autoradiography. High local densities of the AT2 receptor were observed. Comparison of the labelling patterns thus obtained with adjacent sections stained for vimentin, collagen, neurofilaments or acetylcholinesterase revealed that the high densities of AT2 receptor were always associated with fibrous tissue. However, the AT1 receptor was in general evenly distributed over the tissue at low concentrations. Higher local concentrations of this receptor subtype were observed on nervous tissue. The present finding of high densities of the AT2 receptor on fibroblasts at sites of fibrosis may have important clinical implications. Further studies to elucidate the function of this receptor subtype in the heart are therefore essential and the clinical consequences of the use of AT1 antagonists on post-infarction remodelling should be investigated.
J Mol Cell Cardiol 1996 Aug
PMID:Localization of the angiotensin II receptor subtypes in the human atrium. 887 88

Angiotensin II (ANG II) has been implicated in cell growth and differentiation. We investigated the effect of AT2 receptor stimulation on proliferation and morphological differentiation in cells of neuronal origin by using the pheochromocytoma derived cell line, PC12W. ANG II (10(-8)-10(-6) M) inhibited fetal calf serum (FCS)-induced cell proliferation in a concentration dependent manner. In half of the experiments, the epidermal growth factor (EGF) exerted a mitogenic action which was concentration-dependently inhibited by ANG II. In the other half of the experiments, EGF had an antimitogenic effect which was further enhanced by ANG II (maximally at 10(-6) M). Treatment with nerve growth factor (NGF) induced an inhibition of [3H]thymidine incorporation, which was enhanced by ANG II, maximally 25% at the highest concentration. The effects of ANG II on [3H]thymidine incorporation were reflected by those on cell number and were prevented by the AT2 receptor antagonist, PD123177, but not influenced by the AT1 receptor antagonist, losartan. The ANG II-induced inhibition of cell proliferation was paralleled by morphological differentiation in response to daily treatment with ANG II. ANG II also enhanced low-dose NGF-induced neurite formation. Again, these effects of ANG II were abolished by the AT2 receptor antagonist, PD123177. Our data in PC12W cells show that the AT2 receptor not only inhibits growth factor-induced proliferation and enhances the NGF-mediated growth arrest but also induces morphological differentiation in cells of neuronal origin. These findings strongly support the hypothesis that the AT2 receptor promotes differentiation in neuronal cells.
Mol Cell Endocrinol 1996 Aug 30
PMID:The angiotensin II AT2 receptor inhibits proliferation and promotes differentiation in PC12W cells. 889 48


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