Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin II is a potent vasoconstrictor that is important in the control of systemic blood pressure. All the hemodynamic effects of angiotensin II result from the AT1 receptor which has the structural features of a seven transmembrane receptor. Both in cultured rat aortic smooth muscle cells and rat glomerular mesangial cells, angiotensin II stimulates the rapid tyrosine phosphorylation of phospholipase C-gamma 1 (PLC-gamma 1). Tyrosine kinase inhibitors that block this phosphorylation also block the angiotensin II-mediated production of 1,4,5 inositol trisphosphate (1,4,5-IP3) and the intracellular release of Ca2+. The cellular tyrosine kinase c-src appears to play a critical role in the angiotensin II-stimulated tyrosine phosphorylation of PLC-gamma 1 and the generation of 1,4,5-IP3. We have also found that angiotensin II stimulates the tyrosine phosphorylation and activation of the JAK family of intracellular kinases. This in turn activates the STAT family of transcription factors. Angiotensin II, working through the AT1 receptor, uses tyrosine phosphorylation as a mechanism to convey signals from the cell surface to the cell nucleus.
 ...
PMID:Angiotensin II signalling events mediated by tyrosine phosphorylation. 877 37

This study demonstrated the existence of a specific binding site for angiotensin IV in porcine aortic endothelial cells. Non-equilibrium kinetic analyses at 37 degrees C allowed the calculation of a kinetic Kd of 0.44 nM. Pseudo-equilibrium saturation binding studies at 37 degrees C for 90 min indicated the presence of a single high-affinity site (Kd = 3.87 +/- 0.60 nM), saturable and abundant (Bmax = 9.64 +/- 1.44 pmol/mg protein). Competitive binding studies demonstrated the following rank order of effectiveness: angiotensin IV > angiotensin III > angiotensin II > angiotensin I > angiotensin II-(1-7), while 2-n-butyl-4-chloro-5-hydroxymethyl-1 [(2'-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl] imidazol (DuP 753: losartan), 1-(4-amino-3-methyl-phenyl) methyl-5-diphenylisoethyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-C] pyridine-6-carboxylic acid (PD 123177) or nicotinic acid-Tyr-(N alpha -benzyl-oxycarbonyl-Arg) Lys-His-Pro-Ile-OH (CGP 42112A) were inactive at the concentration of 100 microM. This binding site is, therefore, distinct from angiotensin II receptors, AT1 and AT2. Addition of the divalent cations Mg2+, Mn2+ or Ca2+ to the incubation buffer resulted in 90-95% inhibition of the [125I]angiotensin IV-specific binding to porcine aortic endothelial cells. Furthermore, the chelator, EGTA, at 5 mM increased the number of binding sites (Bmax = 17.8 +/- 2.5 pmol/mg protein), with no change in affinity (Kd = 5.7 +/- 1.3 nM). Exposure of porcine aortic endothelial cell membranes to the non-hydrolyzable GTP analog, GTP gamma S, had no effect on [125I]angiotensin IV binding. The presence of a high concentration of binding sites for angiotensin IV in porcine aortic endothelial cells suggests that this peptide may play an important role in the modulation of the cardiovascular system.
 ...
PMID:Pharmacological characterization of a specific binding site for angiotensin IV in cultured porcine aortic endothelial cells. 881 53

Angiotensin IV (Val Tyr Ile His Pro Phe), administered centrally, increases memory retrieval and induces c-fos expression in the hippocampus and piriform cortex. Angiotensin IV binds to a high affinity site that is quite distinct in pharmacology and distribution from the angiotensin II AT1 and AT2 receptors and is known as the AT4 receptor. These observations suggest that the AT4 receptor may have multiple central effects. The present study uses in vitro receptor autoradiography, and employs [125I]angiotensin IV to map AT4 receptors in the macaca fascicularis brain. The distribution of the AT4 receptor is remarkable in that its distribution extends throughout several neural systems. Most striking is its localization in motor nuclei and motor associated regions. These include the ventral horn spinal motor neurons, all cranial motor nuclei including the oculomotor, abducens, facial and hypoglossal nuclei, and the dorsal motor nucleus of the vagus. Receptors are also present in the vestibular, reticular and inferior olivary nuclei, the granular layer of the cerebellum, and the Betz cells of the motor cortex. Moderate AT4 receptor density is seen in all cerebellar nuclei, ventral thalamic nuclei and the substantia nigra pars compacta, with lower receptor density observed in the caudate nucleus and putamen. Abundant AT4 receptors are also found in areas associated with cholinergic nuclei and their projections, including the nucleus basalis of Meynert, ventral limb of the diagonal band and the hippocampus, somatic motor nuclei and autonomic preganglionic motor nuclei. AT4 receptors are also observed in sensory regions, with moderate levels in spinal trigeminal, gracile, cuneate and thalamic ventral posterior nuclei, and the somatosensory cortex. The abundance of the AT4 receptor in motor and cholinergic neurons, and to a lesser extent, in sensory neurons, suggests multiple roles for the AT4 receptor in the primate brain.
 ...
PMID:Distribution of AT4 receptors in the Macaca fascicularis brain. 881 7

Most cell types, including vascular smooth muscle cells and rat kidney mesangial cells, are controlled mainly by two types of cell surface receptors: (a) single membrane-spanning tyrosine kinase receptors for growth factors and (b) seven-transmembrane G-protein linked receptors for vasoactive peptides such as angiotensin II, vasopressin, and endothelin. These vasoactive peptide hormones also act as growth factors in normal and abnormal cell development. However, in contrast to the growth factor receptors (e.g., epidermal growth factor receptor and platelet-derived growth factor receptor), the G-protein linked receptors, such as the angiotensin II AT1 receptor, lack cytoplasmic tyrosine kinase domains. Nevertheless, angiotensin II has recently been demonstrated to cause increased tyrosine phosphorylation of numerous proteins in several cellular systems. For example, angiotensin II has been reported to induce the tyrosine phosphorylation of the gamma-isoform of phospholipase C, pp120, pp125FAK, and members of the janus kinase/signal transducer and activator of transcription pathway. Furthermore, angiotensin II seems to modulate the activity of the soluble cytoplasmic tyrosine kinase pp60c-src, and this tyrosine kinase has been implicated in the phosphorylation of some of the above proteins. Understanding the biochemistry of tyrosine phosphorylation involved in G-protein coupled receptors, such as the AT1 receptor, may therefore lead to the development of new pharmacological interventions important in cardiovascular diseases.
 ...
PMID:The role of tyrosine phosphorylation in angiotensin II mediated intracellular signaling and cell growth. 882 Apr 3

Mechanical stress plays a pivotal role in the development of cardiac hypertrophy during hemodynamic overload, and angiotensin (Ang) II secreted from stretched myocytes plays an important role in mechanical stretch-induced hypertrophy. In the present study, we examined stretch-induced expression of Ang II receptors in an in vitro stretch model using 1-day-old rat myocytes. Both Ang II type 1 receptor (AT1-R) and type 2 receptor (AT2-R) mRNA levels were upregulated by myocyte stretching with similar time courses: significant increases were evident 6 hours after stretching, maximal levels (2.8- and 3.3-fold, respectively) were observed at 12 hours, and these were sustained for up to 18 hours. Ang II receptor expression in fibroblast-rich cultures was not affected by stretching. Conditioned medium in which myocytes were stretched for 12 hours significantly downregulated AT1-R and AT2-R mRNA levels in recipient myocytes, and this effect was almost completely blocked by AT1-R antagonists but not AT2-R antagonists. Stretch-induced expression of AT1-R and AT2-R mRNAs was further increased by 27% and 31%, respectively, after pretreatment with AT1-R antagonists, suggesting that Ang II secreted from stretched myocytes downregulates both AT1-R and AT2-R. Western blot and binding assays showed that the number of AT1-Rs and AT2-Rs increased by 2.4- and 2.6-fold, respectively, without affecting receptor affinities. Inositol phosphate response to 0.5 mumol/L Ang II was enhanced 2.1-fold in stretched myocytes. Nuclear runoff assays and treatment with actinomycin D revealed that stretch-induced upregulation of AT1-R was mainly due to increased transcription, whereas that of AT2-R resulted from a stabilizing effect on AT2-R mRNA metabolism. Stretch-induced changes in levels of Ang II receptors were inhibited by genistein but not by H-7, staurosporin, and protein kinase C depletion or by BAPTA-AM. Exposure to cycloheximide did not affect stretch-induced changes. These findings indicate that nonsecretory pathways activated by myocyte stretching upregulate the expression of Ang II receptor subtypes transcriptionally and posttranscriptionally through mechanisms involving stretch-activated tyrosine kinases independently of de novo protein synthesis and that the AT1-R-mediated action of Ang II is functionally enhanced in stretched cardiac myocytes.
 ...
PMID:Mechanical stretch induces enhanced expression of angiotensin II receptor subtypes in neonatal rat cardiac myocytes. 883 15

The unilateral microinjection of the cholinergic agonist carbachol (CCh) directly into the posterior hypothalamic nucleus (PHN) of conscious rats evokes a dose-dependent increase in mean arterial pressure (MAP). Blockade of peripheral alpha-adrenoceptors and V1-vasopressin receptors completely inhibits this response, suggesting that the increase in MAP is mediated by increases in sympathoadrenal excitation and circulating vasopressin. Combining beta-adrenoceptor blockade with alpha-adrenoceptor and V1-vasopressin receptor blockade results in the return of a pressor response. To determine if neuropeptide Y (NPY) might be responsible for this increase, the putative NPY and irreversible alpha 1-adrenoceptor antagonist benextramine was added to alpha 2- and beta-adrenoceptor and V1-vasopressin receptor blockade provided by yohimbine, propranolol, and [D(CH2)5-Tyr(Me)]AVP (AVPX), respectively. Benextramine noncompetitively inhibited the pressor response to intravenous injection of NPY and the increase in MAP evoked by CCh microinjection into adrenergic and V1-vasopressin receptor-blocked rats, whereas benextramine competitively inhibited the pressor response to angiotensin II (AII). Furthermore, the combination of losartan, the selective AT1-AII receptor antagonist that completely blocked the increase in MAP evoked by intravenous AII, and adrenergic and V1-vasopressin receptor antagonists did not attenuate the pressor response evoked by CCh microinjection into the PHN or the increase in MAP evoked by intravenous injection of NPY. These results indicate that AII was not responsible for the CCh-evoked increase in MAP in the presence of adrenergic and V1-vasopressin receptor blockade. The similarity in the antagonism of the increase in MAP evoked by intravenous NPY injection and by CCh microinjection into the PHN of adrenergic- and V1-vasopressin receptor-blocked rats suggests that NPY might be released from sympathetic neurons after activation of the sympathetic nervous system by central administration of CCh into the PHN.
 ...
PMID:Evidence of systemic neuropeptide Y release after carbachol administration into the posterior hypothalamic nucleus. 887 93

Angiotensin II (AII), acting via its G-protein linked receptor, is an important regulator of cardiac, vascular, and renal function. Following injection of AII into rats, we find that there is also a rapid tyrosine phosphorylation of the major insulin receptor substrates 1 and 2 (IRS-1 and IRS-2) in the heart. This phenomenon appears to involve JAK2 tyrosine kinase, which associates with the AT1 receptor and IRS-1/IRS-2 after AII stimulation. AII-induced phosphorylation leads to binding of phosphatidylinositol 3-kinase (PI 3-kinase) to IRS-1 and IRS-2; however, in contrast to other ligands, AII injection results in an acute inhibition of both basal and insulin-stimulated PI 3-kinase activity. The latter occurs without any reduction in insulin receptor or IRS phosphorylation or in the interaction of the p85 and p110 subunits of PI 3-kinase with each other or with IRS-1/IRS-2. These effects of AII are inhibited by AT1 receptor antagonists. Thus, there is direct cross-talk between insulin and AII signaling pathways at the level of both tyrosine phosphorylation and PI 3-kinase activation. These interactions may play an important role in the association of insulin resistance, hypertension, and cardiovascular disease.
 ...
PMID:Cross-talk between the insulin and angiotensin signaling systems. 890 9

Cardiac hypertrophy of diverse etiologies is associated with two remodeling events: an increase in cardiac muscle mass, and the abnormal accumulation of fibrillar collagen, which results in increased myocardial stiffness and eventual ventricular dysfunction. Clinical and animal studies have implicated angiotensin II (A II) as a growth promoter of both cardiac myocytes and fibroblasts during the cardiac remodeling that occurs with hypertension and myocardial infarction. The growth-promoting effects of A II occur, in part, independent of effects on hemodynamic load. Tissue culture studies have shown that cardiac myocytes and fibroblasts are targets for the actions of A II. In these cells. A II activates phospholipases C, D, and A2, leading in turn to the activation of multiple, conventional second-messenger pathways. By an undefined process. A II also increases the tyrosine phosphorylation of cytosolic proteins, and activates the STAT family of transcription factors, which may mediate an inflammatory or stress response. A II has been shown to affect gene expression of cultured cardiac myocytes and fibroblasts, induce either cellular hyperplasia or hypertrophy, and increase expression of other growth factors. Cardiac fibroblasts have been shown to respond to A II with increased expression of integrins and the extracellular matrix proteins, collagen and fibronectin. Recently, stretch of cardiac myocytes was shown to induce hypertrophy, through an autocrine release of A II. All of the aforementioned actions of A II are mediated by the AT1 receptor.
 ...
PMID:The role of the renin-angiotensin system in the pathophysiology of cardiac remodeling. 891 34

1. Male, Long Evans rats were instrumented chronically with pulsed Doppler probes and intravascular catheters to allow assessment of regional haemodynamic changes during i.v. infusion of lipopolysaccharide (LPS, 150 micrograms kg-1 h-1). 2. In the presence of the AT1-receptor antagonists, losartan (10 mg kg-1 + 10 kg-1 h-1), the initial (1-2 h) hypotensive and renal, mesenteric and hindquarters vasodilator responses to LPS were enhanced significantly. Thereafter these effects waned, but between 8-23 h after the onset of LPS infusion, a further fall in mean atrial blood pressure (MAP) and increases in renal and hindquarters flows and conductances occurred. All these changes were significantly greater than seen with losartan or LPS alone, and exceeded the sum of their effects. 3. In the presence of captopril (2 mg kg-1 + 2 mg kg-1 h-1), the initial hypotensive and renal vasodilator responses to LPS were enhanced, but less so than in the presence of losartan. However, the effects of LPS in the presence of losartan and captopril together were not different from those in the presence of losartan alone. These observations indicate that the ability of captopril to inhibit the degradation of bradykinin had no additional influence, and the differences between the effect of captopril and losartan on the initial effects of LPS were probably due to more effective suppression of the action of angiotensin II by losartan. 4. In the absence of LPS, co-infusion of losartan and the non-selective endothelin antagonist, SB 209670 (600 micrograms kg-1 + 600 micrograms kg-1 h-1), caused a substantial, progressive hypotension (-25 +/- 2 mmHg at 24 h) accompanied by increases in renal, mesenteric and hindquarters vascular conductances (31 +/- 13, 44 +/- 9 and 45 +/- 12%, respectively), indicating an involvement of angiotensin II and endothelin in the maintenance of normal cardiovascular status in conscious, Long Evans rats. 5. In the presence of losartan and SB 209670, the initial, LPS-induced fall in MAP (-42 +/- 2 mmHg) was not different from that in the presence of losartan (-39 +/- 4 mmHg), and the increases in renal, in mesenteric, and in hindquarters vascular conductances were similar in the two conditions. However, there was no recovery in MAP, and there were persistent renal, mesenteric and hindquarter vasodilatations. 6. In all experiments involving LPS, administration of the V1- receptor antagonist, d(CH2)5-O-Me-Tyr-AVP (10 micrograms kg-1), 23 h after the start of LPS infusion caused additional hypotension and mesenteric vasodilatation, particularly. This effect was most marked in animals pretreated with losartan and SB 209670. 7. The results indicate that the initial (1-2 h) depressor and dilator effects of LPS infusion in conscious Long Evans rats are opposed by the actions of angiotensins II, rather than endothelin. However, between 2-8 h after the onset of LPS infusion the involvement of endothelin develops and that of angiotensin II fades. By 24 h after the start of infusion of LPS, the pressor and vasoconstrictor actions of endothelin wane, and a role of vasopressin is apparent. At no stage is there clear evidence for an involvement of bradykinin in the haemodynamic sequelae of endotoxaemia in this model.
 ...
PMID:Temporal differences between the involvement of angiotensin II and endothelin in the cardiovascular responses to endotoxaemia in conscious rats. 898 10

1. Angiotensin II (AngII) initiates a variety of cellular responses through activation of type 1 (AT1; with subtypes AT1A and AT1B) and type 2 (AT2) cell surface angiotensin receptors. Both AT1 and AT2 receptors couple to heterotrimeric guanyl nucleotide binding proteins (G-proteins) and generate intracellular signals following recognition of extracellular AngII, but only AT1 is targeted for the rapid ligand-stimulated endocytosis (internalization) typical of many plasma membrane receptors. 2. AT1 endocytosis proceeds through clathrin-coated pits and is independent of G-protein coupling which predicts that the AngII-AT1 receptor complex attains a conformation necessary for interaction with the endocytotic machinery, but separate from receptor signalling activation. 3. The function of AT1 endocytosis and the reason for the disparity between AT1 and AT2 endocytosis is not fully appreciated, but the latter probably reflects differences in the primary amino acid sequence of these two receptor types. 4. For many receptors that undergo internalization, it has been established that internalization motifs (2-6 amino acids, often incorporating crucial tyrosine and hydrophobic amino acids) within the cytoplasmic regions of the receptor mediate the selective recruitment of activated receptors into clathrin-coated pits and vesicles. 5. Mutagenesis studies on the AT1A receptor, aimed at identifying such motifs, reveal that sites within the third cytoplasmic loop and the cytoplasmic carboxyl terminal region are important for AngII-stimulated AT1A receptor endocytosis.
 ...
PMID:Molecular mechanisms of angiotensin II (AT1A) receptor endocytosis. 899 43


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