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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin II type 2 (AT(2)) receptor is highly expressed in the fetal tissues and decreases rapidly after birth. AT(2) receptor is re-expressed in the adult atretic ovarian follicles. Recently, it has been reported that AT(2) receptor mediates apoptosis. Primarily, we have cloned human AT(2) receptor cDNA and mapped it to the X-chromosome. To further analyze the organization and function of the AT(2) receptor gene, in this study we cloned the human AT(2) receptor genomic DNA. Human AT(2) receptor gene is composed of three exons and two introns. Primer extension analysis revealed a putative transcription initiation site at 24 bp downstream from TATA box. Furthermore, we identified a polymorphism (C-A) in 3' untranslated region of exon 3, which may be a useful genetic marker for genetic analysis of human X-linked inherited disease. In this study, we postulated that the patients with premature ovarian failure, which has been reported to be linked with X-chromosome abnormality, have AT(2) receptor mutation that may contribute to the early onset of atresia. We examined the entire coding sequence of this receptor in two different families of sisters with premature ovarian failure (POF) but found no changes in nucleotide sequences.
Mol Cell Endocrinol 1997 Mar 28
PMID:Genomic organization and polymorphism of human angiotensin II type 2 receptor: no evidence for its gene mutation in two families of human premature ovarian failure syndrome. 909 17

Angiotensin II is involved in blood pressure regulation, cell growth and angioneogenesis. The angiotensin receptors which mediate the intracellular effects of angiotensin II are expressed in numerous tissues and cell types. We studied the expression of angiotensin II receptors in cultured human skin fibroblasts derived from a skin biopsy. Angiotensin II binding characteristics were analyzed by radioligand binding assays. The DNA synthesis was assessed by [H]thymidine incorporation assays. Intracellular calcium concentrations were measured by fura-2 spectrofluorometry, and mRNA expression levels were analyzed by northern blot technology. Two distinct angiotensin receptors were detectable on human skin fibroblasts: the AT1 receptor with Kd = 1.0 +/- 0.7 nmol/l and Bmax = 17.9 +/- 0.9 fmol/mg protein, and an angiotensin(1-7) binding site with Kd = 26 +/- 6.6 nmol/l and Bmax = 80.4 +/- 3.5 fmol/mg protein, as shown by competition binding assays using selective angiotensin II receptor antagonists and the heptapeptide angiotensin(1-7). The angiotensin AT1 receptor mRNA was substantially expressed in human skin fibroblasts and was subjected to homologous downregulation. In human skin fibroblasts angiotensin II caused a profound increase in intracellular calcium which was blocked by angiotensin AT1 receptor antagonists such as Exp-3174. Furthermore, both angiotension II and angiotensin(1-7) led to increased DNA synthesis in human skin fibroblasts. In conclusion, cultured human skin fibroblasts express angiotensin AT1 receptors and a putatively new angiotensin receptor activated by angiotensin(1-7), both coupled to signaling pathways involved in DNA synthesis.
J Mol Med (Berl) 1997 Mar
PMID:Characterization of angiotensin receptors on human skin fibroblasts. 910 70

In rat neonatal cardiac fibroblasts and CHO-K1 cells expressing angiotensin type 1 receptors, angiotensin II (AII) rapidly caused a time dependent reduction in the SDS-polyacrylamide gel electrophoretic mobility of Stat3 (Signal Transducer and Activator of Transcription). This was concentration dependent and detected at a low/physiological concentration of AII (1 nM), with initial effect observed as early as 2 min; and maximal at 5 min. The rapid stimulation of Stat3 mobility retardation by AII, paralleled the rapid activation of MAP kinases (mitogen-activated protein kinases), and both were sensitive to the MAP kinase kinase 1 inhibitor, PD98059. Immunoprecipitation of Stat3 from [32P] labeled cells demonstrated a 4-fold increase in Stat3 phosphorylation in response to AII, and phosphoamino acid analysis indicated that phosphorylation occurred on serine residues. Angiotensin II-induced rapid phosphorylation of Stat3 was also sensitive to the MAP kinase kinase 1 inhibitor, PD98059. Treatment of immunoprecipitated Stat3 from AII-treated cells with protein phosphatase- PP-2A, reversed the AII-induced retardation of Stat3 mobility. These results demonstrate that AII rapidly induces Stat3 serine phosphorylation through a MAP kinase kinase 1 dependent pathway. Rapid stimulation of Stat3 serine phosphorylation by AII may have implications in the modulation of its transcriptional activity and gene expression.
Mol Cell Biochem 1997 May
PMID:Angiotensin II stimulates rapid serine phosphorylation of transcription factor Stat3. 914 32

Angiotensin II (Ang II) is an important regulator of aldosterone production by bovine adrenal glomerulosa cells. On these cells Ang II interacts with the AT1 receptor that is coupled to a G protein controlling the activity of phospholipase C. A primary culture of bovine adrenal glomerulosa cells was used to study the internalization-recycling mechanism of the AT1 receptor after stimulation with Ang II. When cells were pretreated with 10 nM Ang II for 30 min at 37 degrees C and binding studies were performed at 12 degrees C we observed a 48% loss in [125I]Ang II binding. Scatchard analysis revealed that this loss in binding translated into a decreased affinity of the AT1 receptor without any loss in the total amount of binding sites. Under the same conditions an important internalization of [125I]Ang II was invariably observed. These observations suggest that a mechanism was at work to recycle the internalized receptors to the cell surface during the binding studies. Following internalization we indeed observed an externalization of [125I]Ang II. This phenomenon relatively rapid at 37 degrees C was much slower at 12 degrees C and completely inhibited at 4 degrees C. When cells were pretreated with 10 nM Ang II for 30 min at 37 degrees C binding assays at 4 degrees C no longer revealed a loss of binding affinity but rather a 54% reduction in the total amount of binding sites. The maximal binding capacity could be recovered during incubations at 12 degrees C. These results reveal the existence of a dynamic recycling process for the AT1 receptor. In accordance with this interpretation the phenomenon was blocked by monensin, a known inhibitor of receptor recycling. These studies suggest that the stimulation of the AT1 receptor sets in motion an internalization-recycling process that seems to be a fundamental aspect of the AT1 receptor transduction mechanism.
Mol Cell Endocrinol 1997 May 16
PMID:Stimulation of the angiotensin II type I receptor on bovine adrenal glomerulosa cells activates a temperature-sensitive internalization-recycling pathway. 920 4

Angiotensin II (Ang II) stimulates pathologic myocardial fibrosis. Cardiac fibroblasts (CFb) and myofibroblasts mediate this response, perhaps in part by indirect production of specific cytokines. We sought to determine if Ang II could stimulate transforming growth factor-beta1 (TGF-beta1) gene expression and protein production in adult rat CFb and two cardiac myofibroblast cell types, scar myofibroblasts (MyoFb) and valvular interstitial cells (VIC). Confluent CFb, MyoFb, and VIC in serum-deprived (0.4% FCS) media were treated with Ang II (10(-7) m for CFb; 10(-9) m for MyoFb, VIC) for 24 h. Untreated cells served as controls. Culture media was collected and TGF-beta1 levels determined in triplicate using a sandwich ELISA. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis was performed to determine TGF-beta1 mRNA expression. Ang II increased CFb (P<0.02) and VIC (P<0.04) TGF-beta1 mRNA expression, while the increase in MyoFb was not statistically significant. MyoFb produced the highest TGF-beta1 levels under control conditions compared to VIC and CFb. Ang II stimulated further TGF-beta1 secretion in VIC and CFb, but not MyoFb. The AT1 receptor antagonist Losartan (10(-7) m) greatly attenuated Ang II-stimulated TGF-B1 secretion and decreased TGF-beta1 immunostaining in VIC. The AT2 receptor antagonist PD123177 (10(-7) m) also decreased secretion and immunostaining of TGF-beta1 in VIC, but to a lesser extent than Losartan. TGF-beta1 secretion by MyoFb was unaffected by Losartan and PD123177, although TGF-B1 immunostaining was absent or greatly decreased, respectively, compared to Ang II-treated MyoFb. Ang II stimulates TGF-beta1 gene expression and/or protein production in cardiac fibroblast-like cells which may act as an autocrine/paracrine stimulus to collagen formation. Furthermore, TGF-beta1 production and secretion in these cells can be modulated by specific Ang II receptor antagonists, suggesting a potential benefit in preventing/attenuating pathologic myocardial fibrosis.
J Mol Cell Cardiol 1997 Jul
PMID:Angiotensin II stimulated expression of transforming growth factor-beta1 in cardiac fibroblasts and myofibroblasts. 923 48

Angiotensin II (Ang II) binds to two different receptor subtypes, AT1 and AT2 receptors. In many cases, receptor stimulation by Ang II is followed by a rapid desensitization of the intracellular signal transduction and a decrease in cell surface receptor number. The present study was designed to examine by immunofluorescence microscopy the cellular trafficking pathways of Ang II and its AT1a and AT2 receptors in human embryonal kidney 293 cells stably expressing these receptor subtypes. Fluorescently labeled Ang II and AT1a receptors were rapidly internalized into endosomes. AT2 receptors were localized in the plasma membrane and did not undergo endocytosis upon agonist stimulation. After removal of agonist, AT1a receptors recycled to the plasma membrane, whereas fluorescently labeled Ang II was targeted to the lysosomal pathway. Even though no further loss of surface receptor was measurable by ligand binding at steady state, fluorescein-Ang II was continuously internalized, and cycling of receptor between endosomal vesicles and the plasma membrane was detected by antibody feeding. These experiments provide evidence for subtype-specific receptor sorting and internalization of Ang II and its AT1a receptor as a receptor-ligand complex, and they suggest that the sequestration of receptors into endosomes is in dynamic equilibrium with receptor cycling to the plasma membrane. Finally, internalization of AT1a receptors and Ang II persists after desensitization mechanisms have attenuated Ca2+ and inositol 1,4,5-trisphosphate signaling.
Mol Endocrinol 1997 Aug
PMID:Intracellular trafficking of angiotensin II and its AT1 and AT2 receptors: evidence for selective sorting of receptor and ligand. 925 18

Angiotensin II (Ang II) stimulates cardiovascular growth and remodeling via AT1 receptors. Recent experiments have shown that Ang II may also exert antiproliferative effects via AT2 receptors. We studied the effects of Ang II on protein and DNA content and synthesis rate in unstimulated and endothelin-1 (ET-1)-stimulated neonatal rat cardiomyocytes and fibroblasts, isolated from 1-3-day-old Wistar strain pups. Total protein and total DNA, as well as [3H]leucine and [3H]thymidine incorporation were measured following incubation with either vehicle, Ang II, ET-1 or Ang II+ET-1, both in the presence or absence of the AT1 receptor blocker losartan or the AT2 receptor blocker PD123319. In myocytes, ET-1 increased total protein (+38% relative to control) as well as [3H]leucine (+66%) and [3H]thymidine (+77%) incorporation. Ang II did not affect any of these parameters, nor did it influence the ET-1-induced responses. However, in the presence of PD123319 Ang II stimulated [3H]leucine (+24%) and [3H]thymidine (+30%) incorporation. In fibroblasts, ET-1 and Ang II did not significantly affect total DNA and [3H]thymidine incorporation. Ang II tended to increase total protein in these cells, an effect which was significant only in the presence of PD123319 (+17%). Ang II stimulated [3H]leucine incorporation (+24%) in fibroblasts. This effect was absent with losartan and enhanced in the presence of PD123319. These data demonstrate that AT1 receptor-mediated proliferative effects of Ang II in neonatal cardiac cells may become apparent only when its AT2 receptor-mediated antigrowth effects are blocked. The net growth effect of Ang II therefore depends on the cellular AT1/AT2 receptor ratio. Ang II does not appear to interfere with ET-1-induced effects.
J Mol Cell Cardiol 1997 Aug
PMID:Angiotensin II-mediated growth and antigrowth effects in cultured neonatal rat cardiac myocytes and fibroblasts. 928 46

Analysis of post-infarct ventricular remodeling consistently shows the accumulation of collagen in failing heart. The goal of this study was to gain insights into the underlying mechanisms of this event. We determined the effect of hypoxia, caused as the result of ischemia, on biological responses including cell viability, basal and growth factor-stimulated proliferative capacity and collagen type I production in cardiac fibroblasts obtained from adult human heart. The cell viability, as examined by light microscopy and analysis of DNA, did not change by hypoxia (2% oxygen). Basal level of protein synthesis, as determined by measuring the incorporation of 3H-leucine, decreased (30%, P<0.05) under hypoxia. Transforming growth factor-beta (TGF-beta1)- and thyroid hormone (T3)-induced increases in protein synthesis did not change under hypoxia. In contrast, basic fibroblast growth factor (bFGF)-stimulated protein synthesis enhanced significantly under hypoxia. Angiotensin II (Ang II)-treatment, which did not induce significant changes in protein synthesis under ambient conditions, led to moderate but significant increase under hypoxia. Basal level of DNA synthesis, as determined by measuring the incorporation of 3H-thymidine into DNA, decreased (32%, P<0.05) under hypoxia. The TGF-beta1-induced inhibition of DNA synthesis which was observed under ambient conditions was reversed [61% (P<0.005) increase under hypoxia]. Under ambient conditions, T3, Ang II and bFGF stimulated DNA synthesis and their effects were enhanced under hypoxia. Northern analysis showed a 46% (P<0.05) increase in the level of pro alpha1(l) collagen mRNA under hypoxia. The TGF-beta1-induced increase in the level of pro alpha1(l) collagen mRNA, under ambient conditions, was not observed under hypoxia. On the other hand, the T3-induced decrease in pro alpha1(l) collagen mRNA was reversed under hypoxia. Ang II- and bFGF-treatment of human cardiac fibroblasts did not cause detectable changes in the level of pro alpha1(l) collagen mRNA under ambient conditions or hypoxia. At the protein level, the amount of immunoreactive collagen type I, as determined by immunoslot blot analysis, was increased (33%, P<0.05) under hypoxia. Treatment of human cardiac fibroblasts with TGF-beta1 and T3 under ambient conditions led to diminished level of collagen type I. Under hypoxia, however, effect of both factors was reversed. The level of immunoreactive collagen type I in Ang II- and bFGF-treated cells, which was comparable to that in untreated cells under ambient conditions, remained unchanged under hypoxia. Together, these results provide evidence that hypoxia regulates growth, proliferative capacity and collagen type I production in human cardiac fibroblasts, and that although hypoxia alone may not be a stimulus for human cardiac fibroblast proliferation, it enhances growth factor-induced DNA synthesis in those cells. Furthermore, hypoxia by increasing the basal levels of collagen type I and by reversing the TGF-beta1- and T3-induced inhibition of collagen type I gene expression in human cardiac fibroblasts can enhance overall collagen type I production. Combinatorial effects of hypoxia on proliferation and collagen type I production in cardiac fibroblasts contribute to the post-infarct remodeling of the collagen matrix in failing human heart.
J Mol Cell Cardiol 1997 Aug
PMID:Hypoxia regulates basal and induced DNA synthesis and collagen type I production in human cardiac fibroblasts: effects of transforming growth factor-beta1, thyroid hormone, angiotensin II and basic fibroblast growth factor. 928 54

The octapeptide, angiotensin II, has a modulatory role on cardiac cellular growth associated with hypertension and in compensatory remodeling following myocardial infarction. The molecular signal transduction pathways that participate in these and other cellular actions in response to angiotensin II are presently being elucidated. The signal transducers and activators of transcription (STAT) pathway directly links cytokine and growth factor receptors with transcriptional activity. We provide evidence that the G protein-linked, angiotensin II, AT1-receptor couples to activation of the STAT pathway in neonatal rat cardiac myocytes. Angiotensin II induces primarily sis-inducing factor (SIF) B and to a lesser extent SIF-C and SIF-A. The EC50 of this response was 40 nM and Stat1 and Stat3 proteins were identified as components of the SIF complexes. Stat1 and Stat3 were tyrosine phosphorylated five-fold and three-fold, respectively, over control levels following angiotensin II treatment of cardiac myocytes. Phosphorylation of Stat1 and Stat3 proteins was rapid (5 min) and sustained (60 min). Jak2 was also tyrosine phosphorylated eight-fold by angiotensin II treatment, and phosphorylated Stat1 and Stat3 proteins co-immunoprecipitated with activated Jak2 kinase. Selective inhibition of Jak2 kinase with AG-490 blocked formation of angiotensin II induced SIF complexes, suggesting that Jak2 kinase is required for cardiomyocyte SIF induction. In addition, Jak2, Stat1 and Stat3 proteins co-immunoprecipitated with the AT1-receptor. These are the first data to demonstrate coupling of a G-protein coupled receptor, AT1, to the JAK-STAT pathway in primary cultured cardiac myocytes and suggest that this pathway may be involved in transcriptional regulation by angiotensin II.
J Mol Cell Cardiol 1997 Sep
PMID:The type I angiotensin II receptor couples to Stat1 and Stat3 activation through Jak2 kinase in neonatal rat cardiac myocytes. 929 74

Pulmonary arterial myocytes were cultured from normotensive and pulmonary hypertensive rats. Microfluorimetry of Ca2+ signals in fluo-3-loaded single myocytes at day 7 of culture was performed by a laser-scanned confocal imaging system. The resting level of cytoplasmic Ca2+ concentration ([Ca2+]i) in vascular myocytes obtained from hypertensive rats was higher than that in cultured myocytes obtained from normotensive rats. Angiotensin II elevated [Ca2+]i in the vascular myocytes cultured from both normotensive and hypertensive rats. However, a rise of [Ca2+]i induced by angiotensin II in the vascular myocytes obtained from pulmonary hypertensive rats was higher than that obtained from normotensive rats. On the other hand, the response of [Ca2+]i to A23187 did not differ between the vascular myocytes cultured from normotensive and hypertensive rats. The present results suggest that the resting and angiotensin II-responsive levels of [Ca2+]i in pulmonary arterial myocytes cultured from pulmonary hypertensive rats are higher than those cultured from normotensive rats.
Res Commun Mol Pathol Pharmacol 1997 Aug
PMID:High responsiveness of cytosolic free calcium concentration to angiotensin II in cultured pulmonary arterial myocytes from pulmonary hypertensive rats. 934 25


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