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

The octapeptide angiotensin II mediates the physiological actions of the renin-angiotensin system through activation of several angiotensin II receptor (AT) subtypes, in particular AT1 (AT1a and AT1b in the case of rodents). Although we and others have generated mutant mice in which the AT1a gene was disrupted, the function of mouse AT1 remains to be fully elucidated, due to the lack of effective tools involving antibodies against AT1 for detecting biological responses in cellular conditions. To avoid these problems, we constructed the hemagglutinin (HA)-tagged mouse AT1a, and stably introduced this recombinant receptor into human embryonic kidney 293-T cells. Radioligand binding of [(125)I] angiotensin II to AT1a was specific, saturable, and reversible. Scatchard analysis demonstrated that the transfected receptor had a dissociation constant of 1.7 nM with a density of 1.2 x 10(5) sites/cells. Angiotensin II stimulated a rapid increase in cytosolic free calcium, and angiotensin II-induced phosphorylation of extracellular signal-regulated kinases (Erk) was found in a dose-dependent manner. After solubilization, Western blot analysis showed specific interactions between an anti-HA antibody and HA-tagged mouse AT1a. Furthermore, a significant proportion of HA-tagged mouse AT1a was specifically immunoprecipitated with this antibody. In the immunocytochemical and electronmicroscopic studies, treatment of this cell line with angiotensin II resulted in decrease in signals of the surface receptors. Based on these results, the cell line established here provides an excellent tool for studying angiotensin II actions mediated through mouse AT1a, at sub-nanomolar concentrations.
Int J Mol Med 1999 Mar
PMID:Expression and characterization of mouse angiotensin II type 1a receptor tagging hemagglutinin epitope in cultured cells. 1002 49

The endothelium controls the tone of the underlying vascular smooth muscle mainly through the production of vasodilator mediators. In some cases, this function is hampered by the release of constrictor substances. The endothelial mediators are also involved in the regulation by the endothelium of vascular architecture and the blood cell-vascular wall interactions. The endothelium-derived factors comprise nitric oxide (NO), prostacyclin, and a still unknown endothelium-derived hyperpolarizing factor(s) (EDHF). In most vascular diseases, the vasodilator function of the endothelium is attenuated. In advanced atherosclerotic lesions, endothelium-dependent vasodilatation may even be abolished. Various degrees and forms of endothelial dysfunction exist, including (1) the impairment of Galphai proteins, (2) less release of NO, prostacyclin and/or EDHF, (3) increased release of endoperoxides, (4) increased production of reactive oxygen species, (5) increased generation of endothelin-1, and (6) decreased sensitivity of the vascular smooth muscle to NO, prostacyclin and/or EDHF. The levels of bradykinin and angiotensin II within the vascular wall are controlled by angiotensin-converting enzyme (ACE). ACE degrades bradykinin and generates angiotensin II. Bradykinin stimulates endothelial cells to release vasodilators. The actions of the kinin are maintained despite endothelial dysfunction, except in very severe arterial lesions. Angiotensin II may be in part responsible for endothelial dysfunction because it induces resistance to the vasodilator action of NO. Thus, impairment of the generation of angiotensin II blocks the direct and indirect vasoconstrictor effect of the peptide. By potentiating bradykinin, ACE inhibitors promote the release of relaxing vasodilator mediators to restore vasodilator function, and to prevent platelet aggregation as well as the recruitment of leukocytes to the vascular wall.
J Mol Cell Cardiol 1999 Jan
PMID:Endothelial dysfunction: from physiology to therapy. 1007 16

To identify ligand-binding domains of Angiotensin II (AngII) type 1 receptor (AT1), two different radiolabeled photoreactive AngII analogs were prepared by replacing either the first or the last amino acid of the octapeptide by p-benzoyl-L-phenylalanine (Bpa). High yield, specific labeling of the AT1 receptor was obtained with the 125I-[Sar1,Bpa8]AngII analog. Digestion of the covalent 125I-[Sar1,Bpa8]AngII-AT1 complex with V8 protease generated two major fragments of 15.8 kDa and 17.8 kDa, as determined by SDS-PAGE. Treatment of the [Sar1,Bpa8]AngII-AT1 complex with cyanogen bromide produced a major fragment of 7.5 kDa which, upon further digestion with endoproteinase Lys-C, generated a fragment of 3.6 kDa. Since the 7.5-kDa fragment was sensitive to hydrolysis by 2-nitro-5-thiocyanobenzoic acid, we circumscribed the labeling site of 125I-[Sar1,Bpa8]AngII within amino acids 285 and 295 of the AT1 receptor. When the AT1 receptor was photolabeled with 125I-[Bpa1]AngII, a poor incorporation yield was obtained. Cleavage of the labeled receptor with endoproteinase Lys-C produced a glycopeptide of 31 kDa, which upon deglycosylation showed an apparent molecular mass of 7.5 kDa, delimiting the labeling site of 125I-[Bpa1]AngII within amino acids 147 and 199 of the AT1 receptor. CNBr digestion of the hAT1 I165M mutant receptor narrowed down the labeling site to the fragment 166-199. Taken together, these results indicate that the seventh transmembrane domain of the AT1 receptor interacts strongly with the C-terminal amino acid of [Sar1, Bpa8]AngII interacts with the second extracellular loop of the AT1 receptor.
Mol Endocrinol 1999 Apr
PMID:Determination of peptide contact points in the human angiotensin II type I receptor (AT1) with photosensitive analogs of angiotensin II. 1019 64

In response to humoral and mechanical stimuli, the myocardium adapts to increased work load through hypertrophy of individual muscle cells. Myocardial hypertrophy is characterized by an increase in cell size in the absence of cell division and is accompanied by changes in gene expression. Angiotensin II (ANG II), the effector peptide of the renin-angiotensin system (RAS), regulates volume and electrolyte homeostasis and is involved in cardiac and vascular growth in rats. In this review, the role of RAS on the myocyte protein synthesis (myocyte hypertrophy) and on the induction of gene expression will be discussed in rat cardiomyocytes in culture. The traditional RAS can be considered as a system in which circulating ANG II is delivered to target tissues or cells. However, a local RAS has also been described in cardiac cells and evidence has been accumulated for autocrine and/or paracrine pathways by which biological actions of ANG II can be mediated. These actions of ANG II are primarily mediated through ANG II receptors of the subtype I (AT1-R). When evaluating the effects of ANG II in situ, both changes in circulating levels and local production have to be taken into account. Discrepant findings on the in vitro effect of ANG II on the protein synthesis in cardiac myocytes are described and can be at least partly be attributed to methodological problems such as assay of the de novo protein synthesis, isolation and the separation procedure of cardiac myocytes. The ANG II-induced hypertrophic effect also depends on the existence of non-myocytes in a cardiocyte culture. In rat cardiocytes ANG II also causes induction of many immediately-early genes (c-fos, c-jun, jun-B, Egr-1 and c-myc) and induces also late markers of cardiac hypertrophy (skeletal alpha-actin and atrial natriuretic peptide expression) and growth factors (TGF-beta1 gene expression). In vivo ANG II via AT1-R, causes not only ventricular hypertrophy, independently of blood pressure, but also a shift to the fetal phenotype of the myocardium. Angiotensin-converting enzyme inhibitors and ANG II receptor antagonists of the subtype I not only induce the regression, but also prevent the development of cardiac hypertrophy in experimental rat models.
J Mol Cell Cardiol 1999 May
PMID:Renin-angiotensin system, hypertrophy and gene expression in cardiac myocytes. 1033 36

In vascular smooth muscle cells, the hormone angiotensin II is thought to cause internalization of the seven-transmembrane domain type 1 angiotensin II receptor (AT1-R) but it also suppresses expression of the receptor mRNA. As for similarly regulated members of this gene superfamily, the relative roles of these processes in receptor down-regulation are not well understood. In this study a recombinant AT1-R mRNA was synthesized in A7r5 vascular smooth muscle cells from a tetracycline-suppressible promoter using a retroviral vector system. Angiotensin II induces a profound internalization of the cell surface AT1-R protein but has no effect on steady-state AT1-R mRNA levels. Shortly after either bolus or prolonged dosing with angiotensin II, cell surface AT1-R expression recovers, indicating the existence of a significant restorative externalization pathway. The extent of this recovery is attenuated markedly when transcription of the recombinant AT1-R gene is suppressed by cotreatment of the cells with anhydrotetracycline. Although agonist-stimulated internalization appears to contribute directly to a loss of AT1-R protein, these observations provide direct evidence that a reduction in AT1-R mRNA content plays a significant role in sustained AT1-R down-regulation.
Mol Pharmacol 1999 Jun
PMID:Relationship between internalization and mRNA decay in down-regulation of recombinant type 1 angiotensin II receptor (AT1) expression in smooth muscle cells. 1034 44

Reactive oxygen species (ROS, free radicals) produced during cardiac ischemia and reperfusion can damage the contractile functions of arteries. The sarcoplasmic reticulum (SR) Ca2+ pump in coronary artery smooth muscle is very sensitive to ROS. Here we show that contractions of de-endothelialized rings from porcine left coronary artery produced by the hormone Angiotensin II and by the SR Ca2+ pump inhibitors cyclopiazonic acid and thapsigargin correlate negatively with the tissue weight. In contrast, the contractions due to membrane depolarization by high KCl correlate positively. Peroxide also produces a small contraction which correlates negatively with the tissue weight. When artery rings are treated with peroxide and washed, their ability to contract with Angiotensin II, cyclopiazonic acid and thapsigargin decreases. Thus, the SR Ca2+ pump may play a more important role in the contractility of the smaller segments of the coronary artery than in the larger segments. These results are consistent with the hypothesis that ROS which damage the SR Ca2+ pump affect the contractile function of the distal segments more adversely than of the proximal segments.
Mol Cell Biochem 1999 Apr
PMID:Effects of peroxide on contractility of coronary artery rings of different sizes. 1039 Nov 35

Angiotensin II (Ang II) and transforming growth factor (TGF) beta1 play a role in vascular remodeling in hypertension. In this process they may interact on various levels, including that of receptor regulation. This consideration prompted the present study on transcriptional regulation of TGF-beta receptors by Ang II and TGF-beta in vascular smooth muscle cells. Transcriptional expression of the components of the TGF-beta system was demonstrated for TGF-beta and for TGF-beta receptors I, II, and III. As measured by quantitative reverse transcriptase polymerase chain reaction, TGF-beta mRNA increased about 2.4-fold in the presence of 40 pM exogenous TGF-beta. Ang II at 10(-6) M increased TGF-beta mRNA 2.5-fold compared to control cells (P<0.05). Ang II also significantly increased TGF-beta protein concentration in the supernatant of confluent vascular smooth muscle cells. Ang II caused the induction of TGF-beta, but short-term experiments showed TGF-beta receptor II mRNA to be differentially regulated by Ang II and TGF-beta; while TGF-beta caused a 40% decrease in TGF-beta receptor II mRNA after 4 h (P<0.05), Ang II caused an increase by about 70%. In contrast, both TGF-beta and Ang II increased TGF-beta receptor I mRNA to about 260% or 180% of controls (P<0.05). TGF-beta effects were abrogated by coincubation with a TGF-beta neutralizing antibody, and Ang II effects were abrogated by losartan, an AT-1 receptor antagonist. Coincubation of Ang II with the TGF-beta neutralizing antibody did not inhibit the effect of Ang II, indicating that the short-term effects of Ang II on the expression of the TGF-beta receptors are not mediated via TGF-beta. Furthermore, Ang II stimulated DNA synthesis even in the presence of the TGF-beta neutralizing antibody. In conclusion, this study indicates (a) that in vascular smooth muscle TGF-beta receptors are regulated on the RNA level by TGF-beta and Ang II, and (b) that Ang II dependent regulation of TGF-beta receptors is at least partially independent of endogenous TGF-beta. Stimulation of the transcriptional expression of TGF-beta receptors by Ang II may increase sensitivity of vascular smooth muscle cells to TGF-beta.
J Mol Med (Berl) 1999 May
PMID:Differential regulation of transforming growth factor receptors by angiotensin II and transforming growth factor-beta1 in vascular smooth muscle. 1042 93

Angiotensin II (AngII) is thought to stimulate aldosterone secretion from bovine adrenal glomerulosa cells in part via activation of protein kinase C (PKC), while adrenocorticotropic hormone (ACTH) functions through increases in intracellular cAMP levels and calcium influx. Rather than using invasive homogenization techniques as in previous studies, we chose to monitor PKC activity in intact glomerulosa cells in situ by measuring the phosphorylation of the endogenous PKC substrate, myristoylated alanine-rich C-kinase substrate (MARCKS). AngII enhanced MARCKS phosphorylation in a rapid, sustained manner; whereas ACTH induced a rapid and sustained inhibition of MARCKS phosphorylation. Studies using pharmacological agents to mimic various signals indicated that the AngII-induced MARCKS phosphorylation was due to PKC activation, and the ACTH-elicited decrease was mediated by increases in calcium influx rather than cAMP production. We propose that changes in the phosphorylation state of MARCKS, an actin-binding protein, may contribute to cytoskeletal rearrangements involved in steroidogenesis.
Mol Cell Endocrinol 1999 Aug 20
PMID:Effects of angiotensin II and adrenocorticotropic hormone on myristoylated alanine-rich C-kinase substrate phosphorylation in glomerulosa cells. 1050 94

Tumor necrosis factor-alpha (TNF-alpha) biosynthesis by the myocardium in response to several diseases has not been solely associated with activation of the immune system but may also serve as a stress response in the context of neurohumoral gene activation. In this regard, beneficial as well as adverse effects of the cytokine on injured myocardium have been reported. TNF-alpha has been suggested to modulate myocyte and fibroblast cell growth and function. Now, in a rat model of acute myocardial infarction TNF-alpha expression and effects on cardiac fibroblast were determined. TNF-alpha was detected in rat hearts with acute myocardial infarction, parallel to the presence of proliferating fibroblasts, at the border zone of the infarct region, to a lesser degree in the infarct zone and was still present in the surviving myocardium. Similarly, the TNF-alpha mRNA level was, compared to sham-operated heart, higher in the infarct area. In the remote myocardium, a trend to an elevated TNF-alpha mRNA level was observed. TNF-alpha stimulated proliferation and expression of fibronectin in fibroblasts isolated from the infarct, non-infarct-region and sham-operated hearts. Angiotensin II is mitogenic for fibroblasts post-myocardial infarction and effects might be mediated indirectly by TNF-alpha. Addition of a neutralising anti-TNF-alpha antibody inhibited angiotensin II stimulated proliferation of fibroblasts only from the infarcted myocardium. The regional differences in TNF-alpha protein and mRNA levels, parallel to proliferating fibroblasts and proliferative effects may foster the reparative, reactive and adverse post-infarct remodeling of the heart.
J Mol Cell Cardiol 1999 Nov
PMID:Tumor necrosis factor-alpha at acute myocardial infarction in rats and effects on cardiac fibroblasts. 1059 Oct 22

The purpose of this study was to look for evidence of changes in angiotensin converting enzyme activity in the renal vascular bed of streptozotocin (STZ)-induced diabetic rats. To assess the activity of the enzyme, we examined angiotensin I- and angiotensin II-induced vasoconstriction in perfused kidneys from controls and diabetic rats. Angiotensin I (3x10(-9) to 3x10(-6) M) induced a dose-dependent vasoconstriction in control kidneys; this response was completely inhibited by losartan (10(-5) M) and markedly inhibited by both captopril (10(-4) M) and indomethacin (10(-5) M). Angiotensin II (10(-10) to 3x10(-7) M) also caused a dose-dependent vasoconstriction in control kidneys; this response was markedly enhanced by 10(-4) M L-NNA, and significantly inhibited by losartan (10(-5) M). Angiotensin I-induced vasoconstriction was slightly greater in STZ-induced diabetic rats than in controls, but the maximal response was unaffected. These results suggest that angiotensin I is rapidly converted to angiotensin II in the renal vascular bed, and that converting enzyme activity in the renal vascular bed may be decreased in STZ-induced diabetic rats.
Res Commun Mol Pathol Pharmacol 1999
PMID:Changes in angiotensin converting enzyme activity in the renal vascular bed of streptozotocin-induced diabetic rat. 1063 11


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