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

The regulation of the AT1 receptor gene was studied in neonatal cardiomyocytes and fibroblasts in vitro. Incubation with angiotensin II (Ang II) resulted in a time-dependent and dose-dependent decrease in AT1 mRNA levels in both cardiomyocytes and fibroblasts. Coincubation with Ang II and the specific AT1 antagonist losartan prevented the decrease in AT1 mRNA whereas the AT2 antagonist PD123319 was ineffective in preventing the decrease in AT1 mRNA. Because Ang II is known to decrease cAMP levels in cardiomyocytes, the role of cAMP in the regulation of the AT1 gene was examined. Treatment with the adenylyl cyclase stimulant forskolin or the cAMP stereoisomer Sp-cAMPS increased AT1 mRNA levels or prevented the Ang II mediated decrease in AT1 mRNA levels. The role of calcium in the regulation of the AT1 gene was determined by incubation with the calcium ionophores A23187 and ionomycin (0.0625-1 microM) which resulted in a profound, dose-dependent decrease in AT1 mRNA levels. Treatment with BAPTA, an intracellular chelator of calcium, prevented the Ang II-mediated decrease in AT1 mRNA. Therefore Ang II is a potent negative regulator of the AT1 gene in cardiomyocytes and fibroblasts via the AT1 receptor. This Ang II mediated decrease in AT1 mRNA is mediated by two complementary mechanisms involving cAMP and intracellular calcium.
J Mol Cell Cardiol 1996 Aug
PMID:AT1 receptor gene regulation in cardiac myocytes and fibroblasts. 887 82

Acute aldosterone production in adrenocortical cells is highly dependent on calcium (Ca2+) and calmodulin (CaM) activation. To determine the role of calmodulin-dependent protein kinase II (CaM kinase II) in human adrenal aldosterone production, the action of KN93 (a specific CaM kinase II inhibitor) on human adrenocortical H295R cells was examined. The stimulation of aldosterone, production by angiotensin II (Ang II) and potassium (K+) were inhibited by KN93 in a concentration-dependent manner with an IC50 of approximately 0.9 and approximately 0.5 microM, respectively. Aldosterone production was also stimulated by treatment with the calcium channel activator Bay K 8644 (Bay K) (1 microM). This production was inhibited in a concentration-dependent manner by KN93 with an IC50 of between 1 and 3 microM. No inhibition by KN93 (0.3-3 microM) or by the calmodulin inhibitor calmidazolium (0.03-0.3 microM) was observed for 22R-hydroxycholesterol (22R-OHChol) stimulation of aldosterone production. Because 22R-OHChol is a substrate for the cytochrome P450 cholesterol side-chain cleavage enzyme (P450scc) and does not require active transport to the mitochondria, these results indicate that KN93 does not directly inhibit P450scc or later steps leading to aldosterone synthesis. To investigate the site of KN93 action further we examined its effect on agonists induction of steroidogenic acute regulatory (StAR) protein, which was recently shown to regulate the movement of cholesterol from the outer to the inner mitochondrial membranes. Induction of StAR protein in H295R cells by Ang II, or Bay K was not affected by co-treatment with KN93 at concentration which blocked steroidogenesis by 60-80%. These results indicate a direct role of CaM kinase II in Ang II and K+ simulation of aldosterone production and support the hypothesis that CaM kinase II may be involved in the process of cholesterol mobilization to the mitochondria.
J Steroid Biochem Mol Biol 1996 Jul
PMID:Role of calmodulin-dependent protein kinase II in the acute stimulation of aldosterone production. 890 26

The efficacy of angiotensin converting enzyme (ACE) inhibitors is well known to prevent the formation of angiotensin II (Ang II) by these agents. The objective of the present study was to evaluate the hemodynamic, biochemical, and morphological responses to Ang II receptor blockade with E-4177, 3-[(2'-carboxybiphenyl-4-yl) methyl]-2-cyclopropyl-7-methyl 3H-imidazol[4,5-b] pyridine, in rats with a healing myocardial infarction that had been induced by the surgical occlusion of the left main coronary artery. The left ventricular weight increased 8 and 12 weeks after infarction in comparison to that in sham-operated rats. Among the rats with experimental infarction, treatment with E-4177 significantly decreased the left ventricular weight. Although the infarct size was not affected by E-4177, its administration ameliorated the elevated end-diastolic pressure and reduced the systolic pressure. The effects of this agent on the levels of Ang II type 1 (AT1) receptor mRNA and ACe mRNA were evaluated in the non-infarcted myocardium by reverse transcriptase polymerase chain reaction and binding assays. Treatment with E-4177 reduced both the elevated AT1 mRNA and the number of Ang II receptors, but not the ACE mRNA or ACE activity. While the receptor affinity remained unchanged with this agent, the collagen concentration was decreased. On the other hand, the depressed Na+/Ca2+ exchange activity was restored in the non-infarcted myocardium at 8 and 12 weeks after injury to the level seen in the sham-operated rats. These findings suggest that the AT1 receptor antagonist, E-4177, has a beneficial effect on the hemodynamics in spite of the lack of any improvement in the infarct size. These observations may be partly attributed to the prevention of angiotensin II formation during the period of post-infarction healing.
J Mol Cell Cardiol 1996 Mar
PMID:Regression of hypertrophy after myocardial infarction is produced by the chronic blockade of angiotensin type 1 receptor in rats. 901 34

Little is known regarding the developmental regulation of the cardiac angiotensin type 1 (AT1) and type 2 (AT2) receptor genes or their role in normal cardiac growth. Regulation of AT1 and AT2 receptor genes were examined using total and poly A + RNA isolated from whole Sprague-Dawley rat hearts. AT1 mRNA levels were 3.5-fold higher in the 19-day-old fetal heart compared to the 90-day-old adult as detected with 2 or 5 microg of poly A + RNA. AT2 mRNA was only detectable with 20 microg of poly A + RNA. AT2 mRNA levels were highest in the 19-day-old fetal heart with no detectable message in the 90-day-old adult heart. Qualitative PCR for AT2 mRNA also could not detect AT2 mRNA in the adult heart. Treatment with the AT1 receptor antagonist losartan for 3 weeks in the 21-day-old rat or for 4 days in the 38-day-old rat resulted in a significant decrease in heart/body weight in both groups and body weight in the 3-week treatment group. AT2 blockade for 4 days with PD123319 or beta-receptor blockade with propranolol for 3 weeks did not alter heart/body weights. Losartan treatment also resulted in a three-fold increase in cardiac AT1 mRNA levels in both the 4-day and 3-week treatment groups compared to controls. We conclude that Ang II, acting primarily, if not exclusively via the AT1 receptor plays a significant role in the regulation of normal cardiac growth in the young rat.
J Mol Cell Cardiol 1997 Jan
PMID:Developmental regulation of angiotensin type 1 and 2 receptor gene expression and heart growth. 904 29

Immunocytochemistry of paraffin-embedded and cryostat sections of eel (Anguilla anguilla) gill showed that angiotensin II receptors (Ang II-R) were present in chloride cells, uniformly distributed in the cytoplasm and on surface membranes. Computerised image analysis of these preparations showed that gills from sea water (SW)-adapted animals had a significantly (3-fold) higher Ang II-R concentration compared with freshwater (FW)-adapted eel gills. Isoelectric focusing gel electrophoresis revealed two Ang II-R isoforms with pI 6.5 and 6.6 that were differentially modulated by environmental salinity: they were equally abundant in SW while in FW the pI 6.6/pI 6.5 ratio was 1.66. Using catalytic cytochemistry with image analysis, gill chloride cell membrane Na+/K+ATPase activity was shown to increase 4-fold in response to SW adaptation. Additionally, perfusion of gills for 30 min with 0.1, 10 or with 100 nM Ang II provoked a dose-dependent increment in Na+/K+ATPase activity in FW, and a biphasic response in SW gills in which activity was significantly increased at low Ang II concentrations but was reduced to basal values at 100 nM. The data suggest that adaptation to sea water significantly increases Ang II-R concentration in the chloride cell and, together with the effects of Ang II on Na+/K+ATPase activity, suggest a role for this hormone in gill NaCl retention. The different responses of Na+/K+ATPase to Ang II stimulation in FW and SW may be attributed to the presence of two receptor subtypes that are differently modulated by salinity and that have opposing effects on Na+/K+ATPase.
J Mol Endocrinol 1997 Feb
PMID:Angiotensin II receptors in the gill of sea water- and freshwater-adapted eel. 906 8

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

Scar tissue found at the site of myocardial infarction (MI) contains phenotypically transformed fibroblast-like cells termed myofibroblasts (myoFb). In injured cardiac tissue, autoradiography and immunolabeling have localized high density angiotensin (Ang) converting enzyme (ACE) and Ang II receptor binding to these cells, suggesting that they may regulate local concentrations of Ang II and transduce signals at this site. Ang II is known to modulate type I collagen gene expression of fibroblasts and myoFb, and to promote fibrous tissue contraction, each of which may contribute to tissue repair. It is unknown whether myoFb themselves generate Ang peptides de novo via expression of angiotensinogen (Ao), an aspartyl protease needed to convert Ao to Ang I, and ACE. We therefore isolated and cultured myoFb from 4-week-old scar tissue of the adult rat left ventricle with transmural MI. In cultured myoFb we found: (a) immunoreactive membrane-bound ACE, cytosolic cathepsin D (Cat-D), and AT, receptors by immunofluorescence and confocal microscopy, (b) mRNA expression for Ao, ACE, and Cat-D, but not renin, by reverse transcriptase-polymerase chain reaction, (c) production of Ang I and II in serum-free culture media; (d) absence of renin activity; (e) a time-dependent conversion of Ao to Ang I by myoFb cytosol, which was inhibited by pepstatin A, but not by renin inhibitor; and (f) significant increase in Ang II production (P < 0.05) by exogenous Ao and Ang I (10 nM), which was significantly blocked by lisinopril (0.1 microM: P < 0.05). Thus, cultured myoFb express requisite components and are able to generate Ang I and II de novo. In an autocrine and/or paracrine manner, Ang II may regulate myoFb collagen turnover and fibrous tissue contraction.
J Mol Cell Cardiol 1997 May
PMID:Cultured myofibroblasts generate angiotensin peptides de novo. 920 23

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

The objective of this study was to determine the effect of angiotensin I (Ang I) treatment in vivo on two major Ca-transport systems-the L-type voltage dependent calcium channel (L-VDCC) and the Na/Ca exchanger in rat heart. For our experiments we used four groups of rats, treated differently with saline, Ang I, the ACE inhibitor enalapril and/or combination of both for 6 days, every 24 h. We observed an increase in the activity, and also in mRNA expression of the Na/Ca exchanger, after repeated administration of Ang I in vivo. The maximal binding capacity of Ca-antagonist PN 200-110, which binds to the alpha 1 subunit of the L-VDCC was elevated from 0.8-1.85 pg/mg protein. mRNA expression of the voltage-dependent calcium channels of L-type system was also upregulated by Ang I administration, but not when enalapril was applied simultaneously with Ang I. These results demonstrate that in vivo application of the Ang I significantly modulates not only the activity, but also expression of the Na/Ca exchanger and the L-VDCC in rat hearts through angiotensin II (Ang II). Since in the in vitro experiments on the isolated cardiomyocytes, Ang II (100 nM) increased the calcium uptake after depolarization, and the AT1 receptor agonist losartan prevented this increase, we assume that this regulation might involve the AT1 receptors.
J Mol Cell Cardiol 1997 Jun
PMID:Angiotensin I modulates Ca-transport systems in the rat heart through angiotensin II. 922 Mar 59

The mechanisms governing the pathological accumulation of collagen in the extracellular matrix following angioplasty are complex, but may involve interactions between endothelium-derived paracrine agents and vascular cellular components. We tested the hypothesis that nitric oxide (NO) directly decreases collagen levels and decreases endothelin (ET-1)-stimulated increases in levels of specific collagen subtypes in coronary vascular smooth muscle cells (VSMC). Cultured VSMC were incubated for 48 h with the NO donor CAS 754 (10(-4) M), ET-1 (10(-8) M), or ET-1 plus CAS 754. In some experiments, angiotensin II (Ang II; 10(-8) M) was utilized in place of ET-1. Soluble collagen types I and III were quantitated with an ELISA method, and cell counts were performed. CAS 754 significantly inhibited cell proliferation (-17+/-2% v control), basal total protein synthesis (-65+/-7% v control), and basal collagen type I levels (-39+/-6% v control), but not collagen type III levels. ET-1 and Ang II both significantly stimulated cell proliferation (26+/-5% v control), total protein synthesis (169+/-6% v control), and collagen type I levels (200+/-11% v control). Ang II, but not ET-1, significantly increased collagen type III levels. Co-incubations of ET-1 and CAS 754 resulted in a significant decrease in cell proliferation, protein synthesis, and collagen levels (-23+/-2% v control, 90+/-5% v control, and 63+/-3% v control, respectively) compared to ET-1 alone. In contrast, co-incubation of Ang II and CAS 754 had no significant effect on cell proliferation, protein synthesis, and collagen levels seen with Ang II alone. These results demonstrate that NO inhibits basal collagen levels and cell division. Additionally, NO alters ET-1 stimulation of VSMC proliferation, protein synthesis, and production of extracellular matrix components. Thus, an imbalance in key endothelium-derived compounds could significantly impact upon extracellular matrix deposition following mechanical revascularization.
J Mol Cell Cardiol 1997 Jul
PMID:Nitric oxide modulates basal and endothelin-induced coronary artery vascular smooth muscle cell proliferation and collagen levels. 923 33


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