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

In aware of the well-known altered vascular responsiveness in the diabetic vasculature, this study aimed to compare the haemodynamic and PGI2 releasing effects of angiotensin in metabolically healthy (12) and alloxan-(560 umol/kg) diabetic (12) dogs as well as to analyze the role of vascular adrenoceptors in this. In vivo the effect of intracoronarially administered angiotensin (63-125-250-500-1000 pmol/kg/min) on coronary blood flow, mean arterial blood pressure, myocardial contractile force and heart rate was investigated without and with pretreatment of 2 umol/kg phentolamine. In vitro PGI2 release by isolated coronary rings was induced by 50 nmol/l angiotensin before and after pretreatment with 5 umol/l phentolamine and measured by radioimmunoassay. Angiotensin enhances dose-dependently both the mean arterial blood pressure and coronary blood flow, while it provokes a considerable (p < 0.05) increase of PGI2 formation by isolated coronary arterial rings. These alterations could be prevented by phentolamine administration both in vivo and in vitro, while this drug did not affect the angiotensin-induced enhancement of diabetic coronary blood flow. On the other hand the increase of blood pressure by angiotensin was found to be more (p < 0.05) expressed in diabetes and it could be further potentiated by phentolamine. PGI2 synthesis by isolated diabetic coronary rings could not be modified either by angiotensin alone or in combination with phentolamine. On the basis of above data, the lack of stimulated vascular PGI2 formation mediated by alpha-adrenergic mechanisms is supposed to causatively contribute to the diminished sensitivity of diabetic coronary arteries to vasodilation.
Mol Cell Biochem
PMID:Role of vascular adrenergic mechanisms in the haemodynamic and PGI2 stimulating effects of angiotensin in diabetic dogs. 897 51

Recent studies suggest that angiotensin II (angiotensin) may be involved in the regulation of metabolism of the cardiac extracellular matrix (ECM). Two major components of ECM are collagen types I and III which play an important role in maintaining the structure and function of the heart. Although the cellular metabolism of collagen is very complex (especially at the posttranslational level), we chose to address events that occur relatively early in the synthesis of cardiac collagen molecules. To gain an understanding of the role of angiotensin (12, 24, and 48 micrograms/kg/h) on adult heart and cultured neonatal cardiac fibroblasts. The steady-state mRNA abundance of collagen type I and III was monitored using Northern blot analysis in both left and right ventricular samples at day 3 of angiotensin infusion and in cultured cardiac fibroblasts stimulated with angiotensin. In all mRNA abundance studies, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) signal was used to normalize the data for possible differences in loading and/or transfer of total RNA. Both collagen types I/GAPDH and III/GAPDH mRNA signal ratios were increased significantly in left ventricle in all dose regimens used for angiotensin infusion. Only the collagen type I/GAPDH mRNA signal ratio was increased in right ventricle with angiotensin infusion. Angiotensin (10(-7)-10(-5) M) had no effect on the steady-state mRNA abundance of collagen genes in cultured neonatal cardiac fibroblasts after 24 h treatment in serum-free conditions. Our results confirm that infusion of angiotensin may upregulate steady-state collagen gene mRNA abundance in the heart. Angiotensin had no observable effect on collagen mRNA abundance in neonatal fibroblast culture. An explanation for the current results may be that angiotensin causes the release of undefined factors from cardiac myocytes, and that these secondary factors may be involved in either the activation of collagen gene transcription or in alteration of stability of collagen mRNA transcripts via a paracrine mechanism. Although our results indicate hemodynamic loading may potentiate the action of angiotensin, this scenario is unlikely as collagen type I gene expression was increased in the normotensive right ventricle.
Mol Cell Biochem
PMID:Effect of angiotensin II on myocardial collagen gene expression. 897 62

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

Myofibroblasts (myoFb) are cells responsible for fibrous tissue formation in injured systemic organs such as the heart. Cultured myoFb, obtained from rat cardiac scar tissue, express genes that encode components requisite for angiotensin (Ang) II generation, which in turn regulates myoFb collagen turnover in an autocrine/paracrine manner. In this study, we tested the hypothesis that these wound-healing fibroblast-like cells and locally generated Ang II are involved in other repairing tissue. To test this hypothesis, we used a granuloma pouch model, where a subcutaneous air sac is created followed by injection of croton oil. Pouch tissue was collected at days 4, 7, 14 and 21. The presence of myoFb was determined by immunohistochemical alpha-smooth muscle actin (alpha-SMA) labeling and collagen accumulation by picrosirius red staining. Angiotensin converting enzyme (ACE) and Ang II receptor binding were detected by in vitro quantitative autoradiography using 125I-351A and 125I[Sar1, Ile8]Ang II, respectively, while Ang II receptor subtype was defined by displacement studies using either an AT1 (losartan) or AT2 (PD123177) receptor antagonist. Cells expressing ACE were determined by immunohistochemistry. Ang II content in pouch tissue was measured by radioimmunoassay following HPLC separation while its capacity to generate Ang II was assessed in tissue bath, with and without exogenous Ang I or lisinopril, an ACE inhibitor. Collagen accumulation in pouch tissue was examined by determining hydroxyproline content in response to lisinopril, AT1 or AT2 receptor antagonists (losartan or PD123177). In pouch tissue, we found: (1) myoFb at day 4 which became more extensive at days 7, 14 and 21; (2) morphologic evidence of collagen deposition evident at day 4, which gradually became more extensive thereafter; (3) ACE and Ang II receptor binding was evident at day 4 and remained invariant on days 7, 14 and 21; (4) the predominant Ang II receptor subtype expressed was AT1; (5) myoFb express ACE and AT1 receptors; (6) picogram quantities of Ang II (per g tissue) was evident on days 7, 14 and 21; and (7) Ang II was generated from Ang I substrate. Lisinopril and losartan, but not PD123177, significantly attenuated pouch weight and accumulation of collagen. Thus, in this model of cutaneous repair, the appearance of myoFb is associated with Ang II generation that regulates fibrogenesis by AT1 receptor binding. Signals involved in the appearance of myoFb remain uncertain. Further studies are required to address the regulation of Ang II generation in pouch tissue of the rat.
J Mol Cell Cardiol 1997 Aug
PMID:Fibrous tissue and angiotensin II. 928 34

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


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