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

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

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

We recently reported that intrarenal vascular AT1 angiotensin II (ANG II) receptors are major determinants of the increased vascular resistance and reactivity to ANG II observed in the kidney of spontaneously hypertensive rats (SHR). We decided to test the hypothesis that, by modifying plasma ANG II levels by inhibiting the ANG II-converting enzyme (ACE) with captopril, we would modify intrarenal ANG II receptors, and therefore the renal vascular response to ANG II. Two approaches were taken: (1) radioligand binding assays were performed on membrane preparations of purified renal microvessels and glomeruli, with displacement of 125I-[Sar-Ile8]-ANG II by specific non-peptide antagonists of AT (losartan) and AT2 (PD 123319): (2) dose-response curves to ANG II on the isolated perfused kidney were studied. Two weeks of captopril treatment significantly reduced blood pressure (BP) and relative heart weight, and increased plasma renin activity. The binding assays showed that renal microvessels and glomeruli expressed a single receptor population (AT1) for ANG II. The density of glomerular AT1 was not modulated by captopril treatment (600 +/- 174 v 573 +/- 97 fmol/mg protein in non-treated and treated SHR respectively); however. AT1 density on the intrarenal arteries increased 3-fold (55 +/- 20 v 154 +/- 30 fmol/mg protein in non-treated and treated SHR respectively. P < 0.05). Experiments with isolated perfused kidneys demonstrated that captopril did not improve the compliance of intrarenal vessels to high flow but increased their reactivity to ANG II (ED50 = 18 nM v 0.5 pM, P < 0.01). We conclude that treatment with an ACE inhibitor increases vascular reactivity to ANG II which may be mediated by an upregulation of renal vascular ANG II receptors.
J Mol Cell Cardiol 1997 Feb
PMID:Effect of angiotensin-converting enzyme two-week inhibition on renal angiotensin II receptors and renal vascular reactivity in SHR. 914 Aug 37

To determine whether angiotensin II (Ang II) activates the suicide program of myocytes, primary cultures of adult rat ventricular myocytes were exposed to 10(-9) M of Ang II, for 24 h. Ang II resulted in a five-fold increase in programmed myocyte cell death (PMCD) documented by the terminal deoxynucleotidyl transferase assay and confirmed by DNA agarose gel electrophoresis. Ang II stimulation was associated with translocation of the epsilon and delta isoforms of protein kinase C (PKC) which was coupled with an increase in cytosolic Ca2+ in the cells. The PKC inhibitor chelerythrine abolished Ang II-mediated increases in cytosolic Ca2+ and PMCD. Similarly, pretreatment of cells with the intracellular Ca2+ chelator BAPTA/AM inhibited the formation of DNA strand breaks. Conversely, the Ca2+ ionophore A23187 markedly increased PMCD. Finally, the AT1 receptor antagonist, losartan, completely blocked Ang II-induced PMCD, whereas the AT2 receptor antagonist, PD123319, did not attenuate this phenomenon. In conclusion, ligand binding of AT1 receptors on myocytes triggers PMCD by a mechanism involving PKC-mediated increases in cytosolic calcium, which result in internucleosomal DNA fragmentation.
J Mol Cell Cardiol 1997 Mar
PMID:Angiotensin II induces apoptosis of adult ventricular myocytes in vitro. 915 47

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

Two nonpeptide ligands that differ chemically by only a single methyl group but have agonistic (L-162,782) and antagonistic (L-162,389) properties in vivo were characterized on the cloned angiotensin AT1 receptor. Both compounds bound with high affinity (K(I) = 8 and 28 nM, respectively) to the AT1 receptor expressed transiently in COS-7 cells as determined in radioligand competition assays. L-162,782 acted as a powerful partial agonist, stimulating phosphatidylinositol turnover with a bell-shaped dose-response curve to 64% of the maximal level reached in response to angiotensin II. Surprisingly, L-162,389 also stimulated phosphatidylinositol turnover, albeit only to a small percentage of the angiotensin response. The prototype nonpeptide AT1 agonist L-162,313 gave a response of approximately 50%. The apparent EC50 values for all three compounds in stimulating phosphatidylinositol turnover were similar, approximately 30 nM, corresponding to their binding affinity. Each of the three compounds also acted as angiotensin antagonists, yet in this capacity the compounds differed markedly, with IC50 values ranging from 1.05 x 10(-7) M for L-162,389 to 6.5 x 10(-6) for L-162,782. A series of point mutations in the transmembrane segments (TMs) of the AT1 receptor had only minor effect on the binding affinity of the nonpeptide compounds, with the exception of A104V at the top of TM III, which selectively impaired the binding of L-162,782 and L-162,389. Substitutions in the middle of TM III, VI, or VII, which did not affect the binding affinity of the compounds, impaired or eliminated the agonistic efficacy of the nonpeptides but with only minor or no effect on the angiotensin potency or efficacy. Thus, in the N295D rat AT1 construct, L-162,782, L-162,313, and L-162,389 all antagonized the angiotensin-induced phosphatidylinositol turnover with surprisingly similar IC50 values (90-180 nM), and they all bound with unaltered, high affinity (22-36 nM). However, L-162,313 and L-162,782 could stimulate phosphatidylinositol turnover to only 20% of that of angiotensin. It is concluded that minor chemical modifications of either the compound or the receptor can dramatically alter the agonistic efficacy of biphenyl imidazole compounds on the AT1 receptor without affecting their affinity, as determined in binding assays, and that a number of substitutions in the middle of the TM segments affect the efficacy of nonpeptide agonists as opposed to angiotensin.
Mol Pharmacol 1997 Feb
PMID:Dual agonistic and antagonistic property of nonpeptide angiotensin AT1 ligands: susceptibility to receptor mutations. 920 36


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