Disease relevance of Agt

• Many lines of evidence have suggested that angiotensin II (Ang II)plays an important role in cardiac hypertrophy [1].
• Angiotensin II (Ang II) activates multiple signaling pathways leading to hyperplasia of cardiac fibroblasts [2].
• Angiotensin (Ang) II-induced organ damage has fascinated students of hypertension since the work of Wilson and Byrom [3].
• The present study sought to determine whether combined AngII and ET receptor blockade improves cardiac remodeling over individual treatments in an experimental model of left ventricular myocardial infarction (LVMI) in the rat [4].
• Endothelin ETA receptor blockade did not attenuate the left ventricular hypertrophy, even though it reduced the hypertensive effect of AngII [5].

Psychiatry related information on Agt

• Water deprivation for 48 h, leading to extracellular hypertonic hypovolemia with elevated circulating AngII concentrations within the physiological range, caused a significant increase in AoGen-specific hybridization signals in the rostral and medial SFO regions [6].
• In these cells, the peak response latency was significantly longer to Ang II than to SP (59.5 +/- 4.7 versus 26.5 +/- 2.4 seconds, p less than 0.0001) [7].
• Central administration of angiotensin IV (Ang IV) analogues attenuates scopolamine-induced amnesia [8].
• Intracerebroventricular (icv) injection of L-arginine (L-arg), the precursor for NO, has previously been shown to attenuate both dehydration- and angiotensin II (Ang II)-induced drinking behavior [9].

High impact information on Agt

• Treatment with the handle region peptide decreased the renal content of Ang I and II, however, and completely inhibited the development of diabetic nephropathy without affecting hyperglycemia [10].
• Metabolic and renal histological changes and the renin-Ang system components in the plasma and kidneys were determined at 8, 16, and 24 weeks following streptozotocin treatment [10].
• Indeed, Sim inhibited cardiac hypertrophy and decreased myocardial Rac1 activity and O2*- production in rats treated with AngII infusion or subjected to transaortic constriction [11].
• Treatments with the Rho inhibitor C3 exotoxin and with cell-permeable superoxide dismutase also decreased AngII-induced O2*- production and myocyte hypertrophy [11].
• We treated neonatal rat cardiac myocytes with angiotensin II (AngII) with and without simvastatin (Sim) and found that Sim decreased AngII-induced protein content, [3H] leucine uptake, and atrial natriuretic factor (ANF) promoter activity [11].

Chemical compound and disease context of Agt

• Myocardial infarction (MI) is associated with activation of the vasoconstrictor peptides, angiotensin II (AngII) and endothelin-1 (ET-1), which are thought to contribute to adverse cardiac remodeling and dysfunction [4].
• 4. The increase in cardiac mass associated with AngII hypertension was similarly attenuated in the two groups receiving bosentan [12].
• Fibrosis was identified by light microscopy in sections stained with collagen specific picrosirius red, while ACE, AngII and BK receptors binding were localized and quantitated by in vitro autoradiography using 125I-351A, 125I[Sar1,Ile8]AngII, and 125I[Tyr8]BK, respectively [13].
• The reduction of systolic blood pressure by losartan supports a role for AngII in the pathogenesis of this form of hypertension, which may be due, at least in part, to the modulation of ET-1 production [14].
• Therefore, we investigated the effects of glucose on Ang II-mediated activation of Janus-activated kinase (JAK)-2, a tyrosine kinase related with myocyte hypertrophy and cytokine and fibrogenetic growth factor overexpression, in ventricular myocytes isolated from nonfailing human hearts (n = 5) and failing human hearts (n = 8) [15].

Biological context of Agt

• Deletion mutation analysis showed that GIT1(SHD) is required for AngII- and EGF-mediated PLCgamma activation (measured by phosphorylation of Tyr783 and inositol 1,4,5-trisphosphate formation) [16].
• These results indicate that Ang II stimulates the nuclear translocation and activation of NFAT by integrated pathways including the activation of Galpha(12/13), Rac, NADPH oxidase, and JNK and that Galpha(12/13)-mediated ROS production is essential for NFAT transcriptional activation [2].
• Co-treatment of cells with SMV (1 microM) inhibited Ang II-induced upregulation of p27 protein [17].
• The data presented in this study not only elucidate Ang II-mediated signaling cascade in mesangial cells but also demonstrate for the first time the modulatory effects of SMV on Ang II-induced signaling pathway at the cell cycle level [17].
• We show evidence that Ang II stimulates oxidative stress directly or indirectly via endothelin 1 and that NFkappaB is upregulated in this model [3].

Anatomical context of Agt

• Here, we show that ROS mediate Ang II-induced activation of nuclear factor of activated T cells (NFAT) in rat cardiac fibroblasts [2].
• Ang II (100 nM) stimulation of rat mesangial cells induced a significant increase in p27 protein expression [17].
• Like the adrenal zona glomerulosa Ang II receptor, binding inhibition studies show that the granulosa cell AT2 receptor binds Ang II and Ang III with high affinity (IC50, approximately 0.5 nM for both peptides), but not Ang-(1-7) (IC50, approximately 0.5 microM) or Ang-(1-5) (IC50, greater than 10 microM) [18].
• Ang II induced neurite outgrowth by 19 +/- 1.6-fold (p < 0.01) [19].
• We used an angiotensin II (Ang II)-dependent model to test the hypothesis that cerivastatin prevents leukocyte adhesion and infiltration, induction of inducible nitric oxide synthase (iNOS), and ameliorates end-organ damage [20].

Associations of Agt with chemical compounds

• Stimulation of Ang II receptor increased the intracellular ROS level in a Rac- and p47(phox)-dependent manner [2].
• Treatment of AT1 receptor-expressing VSMC with AngII resulted in a dose-dependent and time-dependent increase (2- to 4-fold) in (3)H-glucosamine/(35)S-sulfate incorporation, which was abolished by pretreatment with the AT1 receptor antagonist, losartan [21].
• We administered angiotensin (Ang) II receptor type 1 (AT1) blockade (losartan; 10 or 40 mg/kg per day), type II receptor (AT2) blockades (PD123319; 100 mg/kg per day), or angiotensin-converting enzyme (ACE) inhibitor (enalapril; 30 mg/kg per day) to spontaneously hypertensive rats (SHR) from 10 to 20 weeks of age [22].
• Studies from our laboratory and others show that oestrogen reduces angiotensin II (Ang II)-induced water intake by ovariectomized rats [23].
• Ang II receptor-mediated activation of tyrosine phosphatase SHP-1 was assessed by protein tyrosine phosphatase assay [24].

Physical interactions of Agt

• We examined signaling pathways that are responsible for AngII-induced phosphorylation of CRE-binding protein (CREB) at serine 133 that is a critical marker for the activation in rat vascular smooth muscle cells (VSMC) [25].
• In contrast, the stimulatory effect of Ang II/III on Na+ transport is more complex and involves PKC and MAPK/ERK pathways [26].
• Induction of c-Jun gene transcription by Ang II was abolished in PKM, DN-Rac1, and DN-MEKK1, in which Ang II-induced binding of ATF2/c-Jun heterodimer to the activator protein-1 sequence at -190 played a key role [27].
• Assessment of Ang II receptors by 125I-[Sar1Thr8]-Ang II binding showed that the AT1-receptor subtype predominates in the ganglia [28].
• These observations suggest locally generated AngII via ATi receptor binding is correlated to TGF-beta1 expression and synthesis at sites of repair and remote sites in the infarcted rat heart [29].

Enzymatic interactions of Agt

• We also demonstrated that amlodipine or manidipine prevented the Ang II-induced increase in lectin-like oxidized low-density lipoprotein receptor1 (LOX-1) content, thereby restoring control levels [30].
• Ang II phosphorylated the p44mapk/p42mapk in a time-dependent manner, showing a maximum at 3 minutes [31].
• However, dynamin was not tyrosine phosphorylated by AngII treatment and seemed to be distinct from the 100 kD phosphotyrosine protein that was found in Nck immunoprecipitates [32].

Regulatory relationships of Agt

• Ang II-induced nuclear translocation of the green fluorescent protein (GFP)-tagged amino-terminal region of NFAT4 (GFP-NFAT4) was suppressed by p115-RGS or BAPTA but not by diphenyleneiodonium [2].
• In summary, Ang-(1-7) inhibits Ang II-stimulated MAPK phosphorylation in proximal tubular cells [33].
• 2. In 9-week-old male anaesthetized LH rats and normotensive (LL) controls pretreated with an angiotensin-converting enzyme inhibitor (quinapril; 10 mg/kg) and an AT1 receptor antagonist (losartan; 10 mg/kg), angiotensin (Ang) II was infused (30 ng/kg per min) to stimulate AT2 receptors [34].
• 1. The participation of endothelin (ET) in the development and maintenance of hypertension induced by angiotensin (Ang) II was assessed using the non-specific ET receptor antagonist bosentan (30 mg/kg per day) [12].
• The Ang II-induced activation of SP-1 and AP-1 were significantly suppressed by HS treatment [35].

Other interactions of Agt

• Ang II-induced NFAT activation was suppressed by diphenyleneiodonium (an NADPH oxidase inhibitor), dominant negative (DN)-Rac, DN-p47(phox), and an inhibitor of Galpha(12/13) (Galpha(12/13)-specific regulator of G protein signaling domain of p115RhoGEF, p115-regulator of G protein signaling (RGS)) [2].
• It was also shown that SMV, by inhibiting Rac1 activity, reversed Ang II-induced increase in intracellular H2O2 production, Akt activation, and p27 protein expression [17].
• To determine the Ang receptor status in rat mesenteric vessels, AT1 and AT2 receptor mRNA expression was determined by reverse transcription-polymerase chain reaction [36].
• Plasma Ang II levels were significantly reduced in DS/H rats compared with DS/L rats, whereas kidney Ang II contents and AT1 receptor protein levels were similar [37].
• Furthermore, candesartan decreased renal tissue Ang II contents (from 216 +/- 19 to 46 +/- 3 fmol/mL) and ERK1/2, JNK, and BMK1 activities (-45%, -60%, and -70%, respectively) in DS/H rats [37].

Analytical, diagnostic and therapeutic context of Agt

• Plasma and kidney Ang II levels were measured by radioimmunoassay [37].
• Specific primers were constructed and the gene expression of AngII receptor subtypes was investigated by means of reverse transcription-polymerase chain reaction (RT-PCR) [38].
• The present investigation employed laser-Doppler flowmetry to examine the effect of angiotensin II (AngII) and AngIV stimulation of these receptors on cerebral microcirculation in anesthetized Sprague-Dawley rats [39].
• A 3-h period of Ang II treatment enhanced superoxide generation and the expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase protein, as detected by dihydroethidium staining and Western blotting, respectively [30].
• Groups of male spontaneously hypertensive rats (SHRs; n = 25) were given an intravenous injection of either saline, losartan, PD123319, losartan in combination with PD123319, or Sar1-Thr8-Ang II [40].

References