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Query: UNIPROT:P06889 (Mol)
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TGR(mREN2)27 is a transgenic rat harboring the murine Ren-2 gene and exhibit fulminant hypertension and marked heart hypertrophy. In order to study the role of angiotensin II in the increase of cardiac mass, these animals were treated with antihypertensive and non-antihypertensive doses of the angiotensin II receptor AT1 antagonist Telmisartan for 9 weeks. All doses led to significant reductions of heart hypertrophy detected by the evaluation of the diameter of cardiac muscle bundles. We conclude from this study that cardiac hypertrophy in TGR(mREN2)27 is characterized by an increased volume of cardiomyocytes and an unchanged amount of fibrous tissue and that angiotensin II plays an important role in the mechanisms leading to this phenotype.
Mol Cell Biochem
PMID:Reduction of cardiac hypertrophy in TGR(mREN2)27 by angiotensin II receptor blockade. 897 60

Numerous studies suggest that the renin angiotensin system (RAS) is involved in the development of cardiac hypertrophy. In the present study we produced cardiac hypertrophy in rats subjected to abdominal aortic banding and also induced cardiac regression by the administration of an angiotensin converting enzyme (ACE) inhibitor, enalapril, at 3, 10 and 30 mg/kg/day. Each drug was administered to the rats for 6 weeks from 6 weeks after aortic banding. The left ventricular weight significantly decreased at 10 and 30 mg/kg/day of enalapril as well as the systolic blood pressure. Using the reverse transcriptase polymerase chain reaction, the increased levels of ACE and AT1 mRNA were significantly inhibited in the aortic banding rats treated with the above concentrations of enalapril. The ACE activity in both the plasma and heart tissue preparations was significantly inhibited by enalapril. Similar observations were also seen after the administration of angiotensin type 1 receptor blockade, E-4177, into the aortic banding rats. The treatment with enalapril at 3 mg/kg/day did not reduce the left ventricular weight or the systolic blood pressure in the aortic banding rats. However, this low-dose treatment did significantly decrease the left ventricle to body weight ratio in the aortic banding rats without a reduction of the systolic blood pressure. Therefore, using the low-dose enalapril, the ACE activity in plasma was in part inhibited and the levels of ACE mRNA also decreased in the heart tissue of aortic banding rats, while the level of AT1 mRNA showed no such decrease. These results thus indicate that chronic ACE inhibitor at low doses has a beneficial effect on the regression in the pressure-induced cardiac hypertrophy. It is thus assumed that this effect may also contribute to the presence of an alternate pathway for the conversion of angiotensin I to angiotensin II which might also act as a possible mechanism for cardiac regression.
Mol Cell Biochem
PMID:Chronic low-dose treatment with enalapril induced cardiac regression of left ventricular hypertrophy. 897 63

Although increased deposition of collagen proteins has been described after myocardial infarction (MI), little is known of time-dependent transcriptional alteration of specific cardiac collagen sub-types as well as the degradative mechanisms for cardiac collagens in right and left ventricular myocardium remote to large left ventricular infarction. We sought to study collagen mRNA abundance and the deposition of specific collagen subtypes in noninfarcted left and right rat heart muscle at different times after MI. We also assessed the activity of different myocardial matrix metalloproteinases (MMP) using zymography to gain some information about degradative pathways for collagen. Furthermore, we assessed passive compliance properties of the right ventricle in experimental hearts. Finally we investigated the role of the renin angiotensin system in the collagen gene expression by administration of an angiotensin converting enzyme (ACE) inhibitor (ramipril) and an angiotensin II receptor type I antagonist (losartan) in experimental animals. We observed that the mRNA abundance of types I and III collagen were increased 3 days after myocardial infarction in both viable left and uninfarcted right ventricular tissues, that they peaked at 7-14 days, and were maintained at relatively high levels in the 28 and 56 days experimental groups. Stiffness of the right ventricular myocardium was significantly increased in the 56 days experimental group when compared to that of control values. These findings correlated with increased immunohistochemical staining patterns of different collagen species in the surviving right (and left) cardiac interstitium of 14, 28, and 56 day experimental cardiac groups. The elevation of fibrillar collagen mRNA abundance in noninfarcted muscle from ventricular chambers was not significantly altered after treatment of experimental animals with ramipril and losartan for up to 14 days. MMP activity was increased in viable left ventricle at 14, 28 and 56 days and at 14 days in the right ventricle in experimental animals when compared to controls. These results indicated that (1) activation of transcription of collagen types I and III gene occurs in acute and chronic MI, and that fibrillar collagen proteins are deposited in the noninfarcted cardiac interstitium after a lag period relative to increased corresponding mRNA abundance; (2) an increase in MMP activity in chronic experimental hearts indicates that increased collagen deposition may be due to an increment in collagen synthesis rather by reduced degradation of collagen, and that MMP activation may be important in remodeling of the noninfarcted cardiac stroma; (3) an increase of right ventricular stiffness was associated with increased deposition of collagen; (4) as losartan treatment is not associated with any normalization of elevated collagen mRNA abundance, the upregulation of collagen gene expression in this model is not mediated by AT1 receptor; and (5) the reduction of cardiac fibrosis mediated by ACE inhibition and losartan treatment may reside at the post-translational level in cardiac collagen metabolism.
Mol Cell Biochem 1996 Dec 06
PMID:Effect of ramipril and losartan on collagen expression in right and left heart after myocardial infarction. 897 79

A series of non-peptide angiotensin II receptor antagonists was investigated with the aim of developing a 3D QSAR model using comparative molecular field analysis descriptors and approaches. The main goals of the study were dictated by an interest in methodologies and an understanding of the binding requirements to the AT1 receptor. Consistency with the previously derived activity models was always checked to contemporarily test the validity of the various hypotheses. The specific conformations chosen for the study, the procedures invoked to superimpose all structures, the conditions employed to generate steric and electrostatic field values and the various PCA/PLS runs are discussed in detail. The effect of experimental design techniques to select objects (molecules) and variables (descriptors) with respect to the predictive power of the QSAR models derived was especially analysed.
J Comput Aided Mol Des 1996 Dec
PMID:A 3D QSAR CoMFA study of non-peptide angiotensin II receptor antagonists. 900 90

This study was designed to define more precisely the relationship between specific angiotensin receptors and the growth of vascular smooth muscle cells in response to angiotensin II. These experiments employed quiescent A10 cells which were characterized as smooth muscle by the expression of specific contractlle proteins. Cell growth was monitored by measuring the incorporation of metabolic precursors into RNA or DNA. The treatment of A10 cells with angiotensin II (1 microM) stimulated a hypertrophic response as indicated by an increase in RNA synthesis and protooncogene expression in the absence of DNA synthesis. This increase in RNA synthesis could be blocked by PD123319, an AT2 antagonist, but not by losartan, an AT1 antagonist. RT-PCR analysis demonstrated that quiescent A10 cells express only the AT2 receptor while proliferating A10 cells express the AT1a and AT1b receptors in addition to the AT2 receptor. In addition, induction of AT2 receptor-mediated RNA synthesis was prevented by indomethacin, a cyclooxygenase inhibitor. These studies therefore support a direct connection between the AT2 receptor and smooth muscle growth that is mediated, in part, by prostaglandin synthesis.
J Mol Cell Cardiol 1996 Mar
PMID:The angiotensin type 2 receptor mediates RNA synthesis in A10 vascular smooth muscle cells. 901 33

The aim of the present study was to assess the participation of angiotensin II receptors in the triggering mechanism of ischemic preconditioning. Isolated buffer-perfused rabbit hearts were subjected to 40 min of regional ischemia (37 degrees C) followed by 60 min of reperfusion. Ischemic preconditioning was induced with three cycles of 5-min ischemia and 10-min reperfusion given prior to the 40-min ischemic period. Infarct size and ventricular function were assessed. Ischemic preconditioning reduced infarct size to 5.2 +/- 1.2% of the area at risk (mean +/- S.E.M., P<0.001) when compared to controls (26.4 +/- 3.0%), but did not protect against ventricular dysfunction. Activation of angiotensin II receptors with angiotensin II (100 nM) also limited infarct size (9.6 +/- 2.2%, P<O.01 v control group). Inhibition of angiotensin II receptors with [Sar1, Val5, Ala8]-angiotensin II (saralasin, 1 microM) blocked the protection of ischemic preconditioning against necrosis (29.7 +/- 3.2%) while it did not increase infarct size in saralasin-treated control hearts (31.5 +/- 3.9%). Furthermore, inhibition of the AT1 subtype of the angiotensin II receptor with losartan (20 microM), but not inhibition of the AT2 subtype with PD-123,319 ditrifluoroacetate (10 microM), abolished the infarct size-limiting effect of ischemic preconditioning. We conclude that the AT1 angiotensin II receptor participates in ischemic preconditioning. Thus, in the isolated rabbit heart, activation of AT1 receptors must occur before prolonged ischemia for ischemic preconditioning to limit infarction.
J Mol Cell Cardiol 1997 Jan
PMID:Selective blockade of AT1 angiotensin II receptors abolishes ischemic preconditioning in isolated rabbit hearts. 904 28

The gene mutated in ataxia telangiectasia (AT), the ATM gene, has recently been cloned and shown to encode a multi-domain protein with homology to cell-cycle regulators. We report here an intragenic restriction fragment length polymorphism of the ATM gene that is common in the German population with allele frequencies of 0.56 and 0.44, respectively. Observed heterozygosity approximated 50% in healthy individuals as well as in 152 randomly selected breast cancer patients. We present a simple and rapid polymerase chain reaction (PCR)-based assay for this dimorphism that should be useful to trace the inheritance of ATM alleles in ataxia telangiectasia and breast cancer families and to study loss of heterozygosity in primary tumours.
Mol Cell Probes 1997 Feb
PMID:A frequent polymorphism of the gene mutated in ataxia telangiectasia. 907 18

Modulation of ionic Ca2+ currents by dopamine (DA) could play a pivotal role in the control of steroid secretion by the rat adrenal glomerulosa cells. In the present study, we report that DA decreases the T-type Ca2+ current amplitude in these cells. The use of pharmacological agonists and antagonists reveals that this effect is mediated by activation of the D1-like receptors. Modulation by cAMP is complex inasmuch as preincubation of the cells with 8-Br-cAMP or the specific adenylyl cyclase inhibitor, 2',3'-dideoxyadenosine, have no effect per se, but prevent the DA-induced inhibition. The inhibitory effect of DA was abolished by addition of GDPbetaS to the pipette medium but not by pertussis toxin. If a cell is dialyzed with medium containing G alpha(s)-GDP, the inhibitory effect is reduced and cannot be recovered by the addition of GTPgammaS, indicating that the alpha(s) is not involved, but rather the betagamma-subunit. Indeed, DA-induced inhibition was mimicked by G betagamma in the pipette and 8-Br-cAMP in the bath. Similarly, G betagamma release from the activation of the AT1 receptor of angiotensin II did affect the current amplitude only in the presence of 8-Br-cAMP in the bath. The mitogen-activated protein kinase cascade, which can be activated by receptors coupled to Gs, was not involved as shown by the lack of activation of p42mapk by DA and the absence of effect of the mitogen-activated protein kinase inhibitor, PD 098059, on the DA-induced inhibition. Because the binding of G betagamma-subunits to various effectors involves the motif QXXER, we therefore tested the effect of the QEHA peptide on the inhibition of the T-type Ca2+ current induced by DA. The peptide, added to the medium pipette (200 microM), abolished the effect of DA. We conclude that the presence of the G betagamma and an increase in cAMP concentration are both required to inhibit the T-type Ca2+ current in rat adrenal glomerulosa cells.
Mol Endocrinol 1997 Apr
PMID:Inhibition of the T-type Ca2+ current by the dopamine D1 receptor in rat adrenal glomerulosa cells: requirement of the combined action of the G betagamma protein subunit and cyclic adenosine 3',5'-monophosphate. 909 2

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

The ATM protein has been implicated in pathways controlling cell cycle checkpoints, radiosensitivity, genetic instability, and aging. Expression of ATM fragments containing a leucine zipper motif in a human tumor cell line abrogated the S-phase checkpoint after ionizing irradiation and enhanced radiosensitivity and chromosomal breakage. These fragments did not abrogate irradiation-induced G1 or G2 checkpoints, suggesting that cell cycle checkpoint defects alone cannot account for chromosomal instability in ataxia telangiectasia (AT) cells. Expression of the carboxy-terminal portion of ATM, which contains the PI-3 kinase domain, complemented radiosensitivity and the S-phase checkpoint and reduced chromosomal breakage after irradiation in AT cells. These observations suggest that ATM function is dependent on interactions with itself or other proteins through the leucine zipper region and that the PI-3 kinase domain contains much of the significant activity of ATM.
Mol Cell Biol 1997 Apr
PMID:Fragments of ATM which have dominant-negative or complementing activity. 912 50


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