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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Angiotensin II (AII) and the endothelins (ET) are known to be potent trophic stimuli in various cells including cardiomyocytes. In order to characterize further these effects we studied, in neonatal rat ventricular cardiomyocytes, the effects of several endothelin-receptor antagonists and the AT1-receptor antagonist losartan on AII- and endothelin-induced inositol phosphate (IP)-formation (assessed as accumulation of total [3H]-IPs in myo-[3H]-inositol prelabelled cells) and increase in rate of protein synthesis (assessed as [3H]-phenylalanine incorporation). 2. Endothelin (10 pM-1 microM) concentration-dependently increased IP-formation (max. increase at 100 nM ET-1: 130 +/- 14% above basal, n = 25) and [3H]-phenylalanine incorporation (max. increase at 1 microM: 52 +/- 4% above basal, n = 16) with an order of potency: ET-1 > > ET-3. Both effects were antagonized by the ETA/ETB-receptor antagonist bosentan and the ETA-receptor antagonist BQ-123, but not affected by the ETB-receptor antagonist IRL 1038 and the AT1-receptor antagonist losartan. 3. Pretreatment of the cells with 500 ng ml-1 pertussis toxin (PTX) overnight that completely inactivated PTX-sensitive G-proteins did not attenuate but rather enhance ET-1-induced IP-formation. On the other hand, in PTX-pretreated cardiomyocytes ET-1-induced [3H]-phenylalanine incorporation was decreased by 39 +/- 5% (n = 5). 4. All (1 nM-1 microM) concentration-dependently increased IP-formation (max. increase at 1 microM: 42 +/- 7% above basal, n = 16) and [3H]-phenylalanine incorporation (max. increase at 1 microM: 29 +/- 2%, n = 9). These effects were antagonized by losartan, but they were also antagonized by bosentan and BQ-123. 5. In well-defined cultures of cardiomyocytes (not contaminated with non-myocyte cells) All failed to increase [3H]-phenylalanine incorporation: addition of non-myocyte cells to the cardiomyocytes restored All-induced increase in [3H]-phenylalanine incorporation. 6. We conclude that, in rat neonatal ventricular cardiomyocytes, (a) the ET-1-induced increase in rate of protein synthesis (through ETA-receptor stimulation) involves at least two signalling pathways: one via a PTX-insensitive G-protein coupled to IP-formation, and the other one via a PTX-sensitive G-protein, and (b) the trophic effects of All are brought about via local ET-1 secretion upon AT1-receptor stimulation in neonatal rat ventricular non-myocyte cells.
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PMID:Trophic effect of angiotensin II in neonatal rat cardiomyocytes: role of endothelin-1 and non-myocyte cells. 914 95

The proliferation and hypertrophy of renal tubular cells are primary features in the progression of both acute and chronic renal disease often indicating a poor prognosis. Angiotensin II (ANG II), acting alone or in combination with other growth factors, has been implicated in this process. The aims of this study were to identify the importance of both ANG II and serum-derived factors upon cellular DNA synthesis and protein synthesis in renal proximal tubular cells and to identify the roles of the ANG II receptor subtypes in these processes together with the underlying intracellular signalling mechanisms involved. Primary cultures of renal proximal tubular cells were prepared from freshly isolated rat kidney cortex. Cells were cultured in either serum-replete Dulbecco's modified Eagle's/Ham's F12 or serum-deplete defined medium containing insulin, hydrocortisone, sodium selenite, transferrin, and tri-iodothyronine. Cells were incubated with ANG II (10(-10), 10(-8), 10(-6) M) for 24-120 h either alone or in combination with losartan, PD123319, or pertussis toxin. Incubation of proximal tubular cells in the presence of serum and ANG II (10(-8) M) induced a significant early (24 h) increase in DNA synthesis, together with a significant late (96 h) increase in protein content. [3H]thymidine uptake increased by 56% (p < 0.001) and total protein content by 23% (p < 0.05). In defined media, ANG II (10(-8) M) stimulated protein synthesis only. [3H]uridine uptake, [3H]leucine uptake, and total protein content increased by 25, 57, and 17% (p < 0.05), respectively. In both serum-replete and serum-deplete media, the effects upon protein synthesis of ANG II were inhibited by pertussis toxin and losartan, but not by PD123319. ANG II is clearly a potent stimulator of renal tubular cell DNA and protein synthesis-a response mediated via the AT1 receptor coupled to a pertussis toxin sensitive Gi protein.
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PMID:Selective antagonism of the AT1 receptor inhibits the effect of angiotensin II on DNA and protein synthesis of rat proximal tubular cells. 920 86

Cellular processes leading to renal tubular hypertrophy may contribute to the development of progressive renal disease. Angiotensin II (ANG II) is a prime agent that has been linked to the progression of renal disease by a host of mechanisms, including the induction of tubular epithelial hypertrophy and stimulation of extracellular matrix biosynthesis. All components of a functional renin-angiotensin system reside within the renal tubule. Epithelial cells exhibit distinct patterns of growth behavior after stimulation with ANG II (namely, hypertrophy of proximal tubule segments and proliferation of more distal segments). The hypertrophic action of ANG II is mediated through high-affinity AT1-receptors, involves activation of pertussis-toxin sensitive G1 proteins, and depends on a decrease in intracellular cAMP. In addition, ANG II induces sequential activation of MAP kinases and S6 kinase, and leads to activation of early immediate genes and the modulation of a series of cyclins and cyclin-dependent kinases. There is also compelling evidence that the ANG II-induced epithelial hypertrophy and the stimulated-synthesis of collagen type IV are mediated by increased transcription and production of TGF-beta. ANG II-mediated inhibition of protein degradation may further increase protein content. The hypertrophic response to ANG II is greater in medium with high glucose concentration. Blockade of the action of ANG II prevents the renal hypertrophy and the tubulointerstitial fibrosis in animal models of chronic renal diseases (independent of changes in systemic or glomerular hemodynamics), in part through interception of ANG II-mediated induction of TGF-beta expression.
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PMID:Renal tubular hypertrophy induced by angiotensin II. 931 13

Angiotensin II (ANG II) has long been known for its pressor and growth-promoting effects, which are both mediated by the AT1 receptor. By contrast, the AT2 receptor has recently been reported to mediate inhibition of proliferation through as yet undefined mechanisms. We report here that in bovine adrenal fasciculata cells ANG II by itself does not affect growth but inhibits basic fibroblast growth factor (bFGF)-induced DNA synthesis and blocks the cells in G1 phase. Consistent with this, ANG II inhibits cyclin D1 expression and cyclin D1-associated kinase activity. The antimitogenic effect of ANG II is partly mimicked by the AT2-selective agonist CGP-42112. It is also blocked partly and in an additive fashion by the AT1- and AT2-selective antagonists losartan and PD-123319, indicating the contribution of both receptor subtypes to this response. AT1-dependent antiproliferation is selectively blocked by the cyclooxygenase inhibitor indomethacin and restored by prostaglandin E2, whereas AT2-receptor-mediated inhibition of growth is suppressed by the tyrosine phosphatase inhibitors orthovanadate and bpV(pic). Both pathways are, however, pertussis toxin sensitive. We hypothesize that, in fasciculata cells, the AT1 receptor inhibits bFGF-induced proliferation by stimulating prostaglandin synthesis, whereas the AT2 receptor mediates its effect through a pathway that requires protein tyrosine phosphatase activation.
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PMID:ANG II AT1 and AT2 receptors both inhibit bFGF-induced proliferation of bovine adrenocortical cells. 935 77

1. Desensitization of the myocardial beta-adrenergic signal transduction pathway is an important mechanism which is involved in the progression of hypertensive heart disease. The aim of the present study was to evaluate the differential effects of chronic pharmacotherapy with an angiotensin converting enzyme (ACE)-inhibitor, an AT1-receptor antagonist and a direct vasodilator on blood pressure, cardiac hypertrophy and the beta-adrenergic signal transduction. Therefore, transgenic TG(mREN2)27 (TG) rats overexpressing the mouse renin gene were used. This strain is characterized by the development of fulminant hypertension with cardiac hypertrophy. 2. Seven week old heterozygous TG(mREN2)27 rats were treated for 11 weeks with the AT1-receptor antagonist losartan (10 mg kg[-1]), the ACE-inhibitor quinapril (15 mg kg[-1]) and the direct vasodilator hydralazine (30 mg kg[-1]). Untreated TG and normotensive Sprague-Dawley rats (SD) served as controls. 3. TG(mREN2)27-rats were characterized by arterial hypertension (TG 194+/-3.2 mmHg vs SD 136+/-2.9 mmHg systolic blood pressure), increased left ventricular weights (TG 4.3+/-0.3 vs SD 3.0+/-0.1 mg g(-1) body weight), decreased myocardial neuropeptide Y (NPY) concentrations (TG 1143+/-108 vs SD 1953+/-134 pg g(-1) wet weight), reduced beta-adrenoceptor densities (TG 51.1+/-1.9 vs SD 63.4+/-3.7 fmol mg[-1]) as assessed by [125I]-cyanopindolol binding studies, and increased Gi(alpha)-activities (TG 4151+/-181 vs SD 3169+/-130 densitometric units) as assessed by pertussis toxin catalyzed [32P]-ADP-ribosylation. Downregulation of beta-adrenoceptors and increased Gi(alpha) were accompanied by significantly reduced isoprenaline-, Gpp(NH)p- and forskolin-stimulated adenylyl cyclase activity. Catalyst activity as determined by forskolin plus Mn2+ co-stimulation of adenylyl cyclase did not differ between TG(mREN2)27- and SD control-rats. 4. Losartan and quinapril significantly restored systolic blood pressures, left ventricular weights, beta-adrenoceptor densities, myocardial neuropeptide Y-concentrations, adenylyl cyclase activities and Gi(alpha)-activities towards the values in Sprague-Dawley-controls. No differences were observed between the effects of quinapril- and losartan-treatment. In contrast, hydralazine had only minor effects on blood pressure reduction, regression of left ventricular hypertrophy and neuroeffector defects in TG(mREN2)27. 5. In conclusion, direct vasodilatation is not able to overcome the pathophysiological alterations in TG caused by transgene overexpression. In contrast, ACE-inhibitors and AT1-receptor antagonists, which inhibit the renin angiotensin system, equally exert beneficial effects on blood pressure, myocardial hypertrophy and neuroeffector mechanisms. Modulation of the sympathetic tone and resensitization of the beta-adrenergic signal transduction system may contribute to the special effectiveness of these drugs in the treatment of the hypertensive cardiomyopathy.
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PMID:Effects of quinapril, losartan and hydralazine on cardiac hypertrophy and beta-adrenergic neuroeffector mechanisms in transgenic (mREN2)27 rats. 950 80

Angiotensin II (Ang II) stimulates growth and mitogenesis in bovine adrenal glomerulosa cells, but little is known about the signaling pathways that mediate these responses. An analysis of the growth-promoting pathways in cultured bovine adrenal glomerulosa cells revealed that Ang II, acting via the AT1 receptor, caused rapid but transient activation of mitogen-activated protein kinase (MAPK), with an ED50 of 10-50 pM. Although neither Ca2+ influx nor Ca2+ release from intracellular stores was sufficient to activate MAPK, Ca2+ appeared to play a permissive role in this response. A major component of Ang II-induced MAPK activation was insensitive to pertussis toxin (PTX), although a minor PTX-sensitive component could not be excluded. Ang II also induced the rapid activation of ras and raf-1 kinase with time-courses that correlated with that of MAPK. Activation of protein kinase C (PKC) by phorbol 12-myristate 13-acetate was sufficient to activate both MAPK and raf-1 kinase. However, whereas PKC depletion had no effect on Ang II-induced raf-1 kinase activation, it attenuated Ang II-induced MAPK activation. Ang II also stimulated a mobility shift of raf-1, reflecting hyperphosphorylation of the kinase. However, unlike its activation, raf-1 hyperphosphorylation was dependent on PKC and its time-course correlated not with activation, but rather with deactivation of the kinase. Taken together, these findings indicate that Ang II stimulates multiple pathways to MAPK activation via PKC and ras/raf-1 kinase in bovine adrenal glomerulosa cells.
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PMID:Angiotensin II activates mitogen-activated protein kinase via protein kinase C and Ras/Raf-1 kinase in bovine adrenal glomerulosa cells. 952 65

Treatment of renal mesangial cells with the vasoconstrictor angiotensin II stimulates a concentration-dependent increase in stress-activated protein kinase (SAPK) activity as measured by phosphorylation of the substrate c-Jun. Time course studies reveal a transient SAPK activation by angiotensin II which is maximal after 5-10 min of stimulation and rapidly declines thereafter to basal levels within 30 min. Using the highly selective angiotensin II AT1 receptor antagonist valsartan, a concentration-dependent inhibition of angiotensin II-induced SAPK activity is observed, clearly implying the AT1-receptor in this angiotensin II-mediated response. To further elucidate the mechanism involved in angiotensin II-induced SAPK activation, cells were treated with different inhibitors. Genistein, a tyrosine kinase inhibitor, greatly blocks (by 90%) the angiotensin II response, whereas pertussis toxin only partially inhibits angiotensin II-activated SAPK activity (by 76%). A highly potent protein kinase C inhibitor [3-[1-[3-(amidinothio)propyl-1H-indoyl-3-yl]-3-(1-methyl-1H- indoyl-3-yl) maleimide methane sulfonate], Ro 31-8220, as well as protein kinase C depletion from the cells by prolonged phorbol ester pretreatment, fail to inhibit the angiotensin II-induced SAPK activation. In summary these results suggest that angiotensin II AT1-receptor is able to activate the SAPK cascade in mesangial cells by a pathway independent of protein kinase C, but requiring both pertussis-toxin-sensitive and -insensitive G-proteins and tyrosine kinase activation.
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PMID:Angiotensin II stimulation of the stress-activated protein kinases in renal mesangial cells is mediated by the angiotensin AT1 receptor subtype. 957 Apr 79

The present study was designed to determine the cellular signaling mechanisms responsible for mediating the effects of angiotensin II on proximal tubular Na+,K+-ATPase activity. Angiotensin II produced a biphasic effect on Na+,K+-ATPase activity: stimulation at 10(-13) - 10(-10) M followed by inhibition at 10(-7) - 10(-5) M of angiotensin II. The stimulatory and inhibitory effects of angiotensin II were antagonized by losartan (1nM) suggesting the involvement of AT1 receptor. Angiotensin II produced inhibition of forskolin-stimulated cAMP accumulation at 10(-13) - 10(-10) M followed by a stimulation in basal cAMP levels at 10(-7) - 10(-5) M. Pretreatment of proximal tubules with losartan (1nM) antagonized both the stimulatory and inhibitory effects of angiotensin II on cAMP accumulation. Pretreatment of the proximal tubules with pertussis toxin (PTx) abolished the stimulation of Na+,K+-ATPase activity but did not affect the inhibition of Na+,K+-ATPase activity produced by angiotensin II. Pretreatment of the tubules with cholera toxin did not alter the biphasic effect of angiotensin II on Na+,K+-ATPase activity. Mepacrine (10microM), a phospholipase A2 (PLA2) inhibitor, reduced only the inhibitory effect of angiotensin II on Na+,K+-ATPase activity. These results suggest that the activation of AT1 angiotensin II receptors stimulates Na+,K+-ATPase activity via a PTx-sensitive G protein-linked inhibition of adenylyl cyclase pathway, whereas the inhibition of Na+,K+-ATPase activity following AT1 receptor activation involves multiple signaling pathways which may include stimulation of adenylyl cyclase and PLA2.
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PMID:Angiotensin II AT1 receptor/signaling mechanisms in the biphasic effect of the peptide on proximal tubular Na+,K+-ATPase. 960 7

In C9 (Clone 9) liver cells, angiotensin 11 increased the intracellular Ca2+ content, inositol phosphate production and c-fos mRNA expression. Other angiotensins were also active with the order of potency being angiotensin II = angiotensin III >> angiotensin I > angiotensin IV. Losartan, but not PD 123177 (1-(4-amino-3-methyl)-5-diphenylacetyl-4,5,6,7-tetrahydro-1H-imida zo [4,5c]pyridine-6-carboxylic acid), blocked the effects of angiotensin II. Pertussis toxin did not alter these actions of angiotensin II. These data indicate that the effects were mediated through angiotensin AT1 receptors involving pertussis toxin-insensitive G-proteins. Phorbol myristate acetate was also able to increase c-fos mRNA expression. The action of angiotensin II was consistently greater than that of the active phorbol ester. Staurosporine but not genistein inhibited this effect of angiotensin II. Angiotensin II- and phorbol myristate acetate-induced proto-oncogene mRNA expression was attenuated in cells incubated overnight with the active phorbol ester, which suggests a major role of protein kinase C.
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PMID:Angiotensin AT1 receptors in Clone 9 rat liver cells: Ca2+ signaling and c-fos expression. 987 76

In cultured vascular smooth muscle cells (VSMCs), activation of phospholipase D (PLD) by angiotensin II (Ang II) represents a major source of sustained generation of second messengers. Understanding the molecular mechanisms controlling activation of this pathway is essential to clarify the complexities of Ang II signaling, but the most proximal mechanisms coupling AT1 receptors to PLD have not been defined. Here we examine the role of heterotrimeric G proteins in AT1 receptor-PLD coupling. In alpha-toxin permeabilized VSMCs, GTPgammaS enhanced Ang II-stimulated PLD activation. In intact cells, Ang II activation of PLD was pertussis toxin-insensitive and was not additive with sodium fluoride, a cell-permeant activator of heterotrimeric G proteins, indicating that AT1 receptor-PLD coupling requires pertussis toxin-insensitive heterotrimeric G proteins. Ang II-stimulated PLD activity was significantly inhibited in VSMCs electroporated with anti-Gbeta antibody (56 +/- 5%) and in cells overexpressing the Gbetagamma-binding region of the carboxyl terminus of beta-adrenergic receptor kinase1 (79 +/- 8%), suggesting a critical role for Gbetagamma in PLD activation by Ang II. This effect may be mediated by pp60(c-src), because in beta-adrenergic receptor kinase1 overexpressing cells, pp60(c-src) activation was inhibited, and in normal cells anti-pp60(c-src) antibody inhibited Ang II-stimulated PLD activity. Galpha12 may also contribute to AT1 receptor-PLD coupling because electroporation of anti-Galpha12 antibody significantly inhibited PLD activity, whereas anti-Galphai and Galphaq/11 antibodies had no effect. Furthermore, electroporation of anti-RhoA antibody also attenuated Ang II-induced PLD activation, suggesting a role for small molecular weight G protein RhoA in this response. Thus, we provide evidence here that Gbetagamma as well as Galpha12 subunits mediate AT1 receptor coupling to tonic PLD activation via pp60(c-src)-dependent mechanisms, and that RhoA is involved in these signaling pathways in rat VSMCs. These results may provide insight into the molecular mechanisms underlying the highly organized, complex, chronic signaling programs associated with vascular smooth muscle growth and remodeling in response to Ang II.
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PMID:Angiotensin II receptor coupling to phospholipase D is mediated by the betagamma subunits of heterotrimeric G proteins in vascular smooth muscle cells. 988 8


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