Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously shown that angiotensin II (AII) is a mitogen for neonatal rat cardiac fibroblasts. However, the signaling events that lead to fibroblast cell growth in response to AII remain to be elucidated. Mitogen-activated protein (MAP) kinases are cytosolic serine/threonine kinases which have been shown to be activated in quiescent cells by diverse growth stimuli, thereby being linked to growth regulatory pathways. This study was designed to determine whether MAP-kinase activation occurred in response to AII/receptor coupling in neonatal rat cardiac fibroblasts and the role of MAP-kinase activation in the AII-induced proliferation of these cells. Immunoblot analysis of MAP-kinase isoforms revealed predominantly p44 with less p42 MAP-kinase in rat cardiac fibroblasts. Both isoforms were activated upon stimulation of the cells with AII for 5 min or platelet derived growth factor-BB for 10 min. Angiotensin II stimulated MAP-kinase in a dose-dependent fashion with an EC50 of 2.5 nM. Two minutes following stimulation with 1 microM AII MAP-kinase activity increased from 90 +/- 17.9 to 477.5 +/- 75.9 pmol/min/mg protein, P < 0.05, n = 4. A smaller, sustained, secondary increase in MAP-kinase activity from 37.7 +/- 5.3 to 110.9 +/- 15.3 pmol/min/mg protein, P < 0.05, n = 4, was observed in response to AII between 120-150 minutes following receptor occupancy. The responses to AII were markedly attenuated by the AT1 receptor antagonist EXP3174. Stimulation of the cells with carbachol induced the first but not the second phase of MAP-kinase activity and this compound had no effect on cellular growth. The second phase of MAP-kinase activity 2-2.5 h after AII stimulation, paralleled data demonstrating that a 2-3 h receptor occupancy with AII was necessary to induce DNA synthesis and fibroblast proliferation. These results indicate that AII stimulates a biphasic activation of MAP-kinase by the AT1 receptor and that this pathway may participate in the AII induced mitogenic response in cardiac fibroblasts.
J Mol Cell Cardiol 1995 May
PMID:Angiotensin II is a potent stimulator of MAP-kinase activity in neonatal rat cardiac fibroblasts. 747 73

Angiotensin II (AII) is a growth factor that stimulates protein synthesis and induces cellular hypertrophy in aortic smooth muscle cells (SMC). This trophic effect is mediated by the AT1 subtype of AII receptors. However, very little is known about the cellular signaling pathways involved in this response. In the present study, we examined the role of protein tyrosine phosphorylation in the growth-promoting effects of AII on rat aortic SMC. The addition of AII to quiescent aortic SMC induced tyrosine phosphorylation of multiple substrates, as revealed by antiphosphotyrosine immunoblotting. This response was blocked by preincubation with the AT1-selective antagonist losartan. To explore the functional role of this signaling pathway, we performed experiments with two mechanistically distinct tyrosine kinase inhibitors. Treatment of quiescent aortic SMC with genistein and herbimycin A abolished the stimulatory effect of AII on overall protein tyrosine phosphorylation. Similarly, the two inhibitors prevented AII-induced tyrosine phosphorylation of the cytoskeletal protein paxillin. Under the same conditions, incubation with genistein or herbimycin A did not interfere with AII binding to the AT1 receptor and did not significantly affect AII-stimulated inositol-1,4,5-trisphosphate production and Ca2+ mobilization. In parallel to their selective action on tyrosine phosphorylation, both genistein and herbimycin A completely inhibited AII-stimulated protein synthesis in a dose-dependent manner. In contrast, the two inhibitors were much less potent in preventing the trophic effect of phorbol-12-myristate 13-acetate in these cells. We further demonstrate that genistein and herbimycin A did not prevent mitogen-activated protein kinase activation and c-fos gene induction, which is consistent with the notion that these downstream effectors do not link AII-induced tyrosine phosphorylation to protein synthesis. These results provide evidence that tyrosine phosphorylation has a critical role in cellular hypertrophy and is involved in AII action in vascular SMC.
Mol Pharmacol 1995 Oct
PMID:Involvement of a tyrosine kinase pathway in the growth-promoting effects of angiotensin II on aortic smooth muscle cells. 747 82

Rat aortic smooth muscle cells produced large quantities of nitric oxide (NO) after exposure to interleukin-1 beta, and this was depressed in the presence of the protein kinase C inhibitor bisindolylmaleimide. Intracellular cAMP levels were elevated mildly in cytokine-treated smooth muscle cells, and the presence of forskolin enhanced both the cAMP levels and NO production. Inhibition of GTP:cyclohydrolase I by 2,4-diamino-6-hydroxypyrimidine attenuated NO production by interleukin-1 beta-treated cells. GTP:cyclohydrolase is the regulatory enzyme for de novo tetrahydrobiopterin synthesis, and the latter is a required cofactor for NO synthase activity. Treatment of smooth muscle cells with forskolin induced GTP:cyclohydrolase mRNA expression, and simultaneous treatment of cells with forskolin and phorbol esters elicited NO production. Angiotensin II and arginine-vasopressin, acknowledged agonists for protein kinase C, elicited production of NO by forskolin-treated smooth muscle cells. These observations confirm the importance of GTP:cyclohydrolase activity for NO production by cultured smooth muscle cells and implicate both adenylyl cyclase and protein kinase C in this process.
Mol Pharmacol 1994 Aug
PMID:Simultaneous activation of adenylyl cyclase and protein kinase C induces production of nitric oxide by vascular smooth muscle cells. 752 13

Angiotensin II (AGII) and thromboxane A2 (TXA2), potent vasoconstrictors, augmented the production of the precursor of tissue procollagenase/promatrixmetalloproteinase-1 (proMMP-1) and DNA synthesis in cultured human aortic smooth muscle cells (SMC) significantly compared with that in untreated SMC. Moreover, AGII and TXA2 stimulated hydrolysis of phosphoinositides and subsequent formation of inositol triphosphate (IP3), leading to an increase in the intracellular free Ca2+ concentration. These results suggest that the production of proMMP-1 increased by AGII and TXA2 in intimal SMC in relation to cell proliferation plays a role in arterial reconstruction in vascular diseases.
Biochem Mol Biol Int 1995 Feb
PMID:Effect of angiotensin II and thromboxane A2 on the production of matrix metalloproteinase by human aortic smooth muscle cells. 766 80

Angiotensin II (Ang II) is an essential component of the renin-angiotensin system and is partially responsible for the maintenance of hypertension. Two major receptor subtypes have been defined for Ang II and have been detected in the heart of various species. Most of the known functions of Ang II are mediated via the AT1 subtype, whereas the function of the AT2 receptor remains ill defined. In this study we aimed to localize both receptor subtypes in the rabbit heart using film and light microscope autoradiography as well as radioligand binding assays on membranes. Total receptor densities in the atrium and nervous tissue were respectively four and nine times greater than in the ventricle. Conductive tissue shows a density between that of atrial and nervous tissue. In the ventricle, approximately 20% of the Ang II receptors were AT2. This receptor subtype was almost totally absent from nervous, conductive and atrial tissue. The limited resolution of the microscope autoradiography method did not allow us to specify the exact cell-type at this stage.
J Mol Cell Cardiol 1995 Jan
PMID:Localization of angiotensin II receptor subtypes in the rabbit heart. 776 Mar 66

To address conflicting reports concerning the number of angiotensin II (AII) receptor type 1 (AT1) coding loci in vertebrates, Southern blot analysis was used to determine the genomic representation of AT1 receptor genes in animals comprising a divergent evolutionary spectrum. The data demonstrate that the AT1 receptor gene is present as a single genomic copy in a broad spectrum of animals including human, monkey, dog, cow, rabbit, and chicken. In contrast, members of the rodent taxonomic order contain two genes in their genomes. These two genes may have arisen in rodents as a consequence of a gene duplication event that occurred during evolution following the branching of rodents from the mammalian phylogenetic tree. In order to investigate the properties of the human AT1 receptor in a pure cell system, the recombinant human AT1 receptor was stably expressed in mouse L cells. An isolated cell line, designated LhAT1-D6, was found to express abundant levels of recombinant receptor [430 +/- 15 fmol/mg] exhibiting high affinity [KD = 0.15 +/- 0.02 nM] for [125I][SAR1, Ile8] angiotensin II (SIA). The pharmacological profile of ligands competing for [125I] SIA binding to the expressed receptor was in accordance with that of the natural receptor. Radioligand binding of the expressed receptor was decreased in the presence of the non-hydrolyzable analog of GTP, guanosine 5'-(gamma-thio) triphosphate [GTP gamma S]. Angiotensin II evoked a rapid efflux of 45Ca2+ from LhAT1-D6 cells that was blocked by AT1 receptor specific antagonists. In addition, AII inhibited forskolin-stimulated cAMP accumulation in these cells which was blocked by the AT-1 antagonist. Thus, the LhAT1-D6 cell line provides a powerful tool to explore the human AT1 receptor regulation.
Mol Cell Biochem 1994 Feb 09
PMID:Human AT1 receptor is a single copy gene: characterization in a stable cell line. 804 68

The application of fast atom bombardment (FAB) mass spectrometry to the C-terminal amino acid sequence determination of peptides is reported. FAB mass spectrometric analysis of the peptides formed by carboxypeptidase Y (CPY) digestion conveniently provides information about C-terminal amino acid sequences. In these experiments, we accomplished the determination of C-terminal region amino acid sequence of Bradykinin and Angiotensin II. We describe advantages of the combination experiment of CPY and FAB mass spectrometry for C-terminal region amino acid studies of small peptides. The significant advantages of this method are the ability to study peptides without derivatization and the elimination of the separation step of liberated C-terminal amino acids and peptides. With this method, we could overcome several problems which conventionally happened in C-terminal sequence analysis.
Biochem Mol Biol Int 1994 May
PMID:Application of carboxypeptidase Y and fast atom bombardment mass spectrometry for C-terminal sequencing of small peptides. 808 Dec 13

1. Specific 125I-Sar1, Ile8-Angiotensin II (125I-Sar1, Ile8-AII) binding sites in bovine retinal microvessels were investigated using the quantitative receptor autoradiographic method with pellet sections. 2. A quantitation was made with the computerized radioluminographic imaging plate system, a newly developed and highly sensitive method. Binding characteristics of the retinal microvessels were compared with those of the cerebral microvessels and the retinal macrovessels. 3. We isolated microvessels from the bovine retina and bovine cerebral cortex using the method composed of two-size sievings and high-speed homogenization with a Polytron. The isolated microvessels were composed of capillaries, and the retinal macrovessels contained vessels with smooth muscle. 4. There were specific binding sites for 125I-Sar1, Ile8-AII which were single and of a high affinity, in both the cerebral and the retinal microvessels and the retinal macrovessels. There were no differences in affinity between the vessels, but the retinal microvessels did have a higher density of binding sites than the cerebral microvessels. 5. The method we used is simple and sensitive for detecting and characterizing 125I-Sar1, Ile8-AII binding sites in retinal capillaries. Knowledge of the existence of large numbers of specific binding sites, candidates of physiologically active angiotensin II receptors, aids with understanding the regulatory roles of angiotensin II in the blood-retinal barrier.
Cell Mol Neurobiol 1993 Jun
PMID:Quantitative receptor autoradiographic analysis for angiotensin II receptors in bovine retinal microvessels: quantitation with radioluminography. 824 87

To investigate the contribution of the cardiac renin-angiotensin system to ventricular dilatation after myocardial infarction, we examined the effects of 3-week treatments with an angiotensin converting enzyme inhibitor, delapril, and a selective angiotensin II type 1 (AT1) receptor antagonist, TCV-116, on haemodynamics and ventricular angiotensin II contents in myocardial-infarcted rats. TCV-116 reduced mean aortic pressure, and prevented the increase of right and left ventricular weight, left ventricular end-diastolic pressure and volume of myocardial-infarcted rats, to a similar extent to delapril. Thus, AT1 receptor-mediated action of angiotensin II plays a central role in the development of ventricular dilatation. Angiotensin II contents in the right and non-infarcted left ventricles (6.0 +/- 1.0 and 5.9 +/- 0.7 pg/g tissue, respectively, mean +/- S.E.M.) of myocardial-infarcted rats were not different from those of sham-operated rats. However, angiotensin II contents in the infarcted scar (21.7 +/- 3.5 pg/g) of myocardial-infarcted rats were 4.2-fold higher than those in the left ventricle of sham-operated rats. Delapril reduced angiotensin II contents in the right and non-infarcted left ventricles, and the scar by 48, 81 and 60%, respectively, but did not reduce plasma angiotensin II in myocardial-infarcted rats. TCV-116 also decreased angiotensin II in the right and non-infarcted left ventricles by 57 and 56%, respectively, while increased plasma angiotensin II by 4.3-fold. Thus, the prevention of ventricular dilatation by these two agents was associated with the decrease in ventricular angiotensin II contents. These observations suggest that the cardiac renin-angiotensin system rather than the circulating system may play an important role in ventricular dilatation after myocardial infarction.
J Mol Cell Cardiol 1993 Nov
PMID:Contribution of cardiac renin-angiotensin system to ventricular remodelling in myocardial-infarcted rats. 830 70

A 2046-base pair cDNA clone, homologous to mammalian angiotensin (AT) AT1 receptors, was isolated from a library prepared from adrenal glands of the domestic turkey (Meleagris gallopavo). Sequence analysis of the cDNA insert in clone pTAT2' reveals a 1077-base pair open reading frame predicting a 359-amino acid protein approximately 75% homologous to mammalian AT1 receptors. Saturation radioligand binding studies performed in membranes of COS-7 cells transfected with pTAT2' show high affinity specific binding of 125I-angiotensin II, with a Kd of 172 pM. The rank order of affinities for a series of ligands determined by competition binding studies is angiotensin II > or = [Sar1,Ile8]-angiotensin II > angiotensin III approximately [Sar1,Ala8]-angiotensin II approximately CGP42112A > angiotensin I > Dup753 > PD123177. This rank order of affinity series differs substantially from that for mammalian AT1 receptors and AT2 binding sites. Angiotensin II (100 nM) can stimulate inositol phosphate production similarly in COS-7 cells transfected with pTAT2' and in COS-7 cells transfected with the AT1a receptor cDNA pCa18b. This response in pTAT2'-transfected cells is not attenuated in the presence of 30 microM Dup753. In contrast, this concentration of antagonist attenuates > 90% of the inositol phosphate response to angiotensin II in COS-7 cells transfected with the rat AT1a receptor cDNA. These results demonstrate an avian structural homologue of mammalian AT1 receptors possessing distinct pharmacological properties with both peptide and nonpeptide AT receptor ligands.
Mol Pharmacol 1993 Jul
PMID:A cloned angiotensin receptor isoform from the turkey adrenal gland is pharmacologically distinct from mammalian angiotensin receptors. 834 Dec 66


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>