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

Angiotensin II (ANG II), as a single factor, induces proliferation in a cultured murine mesangial cell line (MMC). This study was undertaken to evaluate a possible influence of atrial natriuretic peptide (ANP) on this ANG II-induced proliferation. ANP (10(-7) M) for 2 min significantly increased intracellular cGMP levels in MMC. This increase in cGMP was totally abolished when cells were preincubated for 5 min with 10(-7) M ANG II. Stimulation of intracellular cGMP formation by sodium nitroprusside was also decreased in the presence of ANG II. The ANG II-mediated inhibition of ANP-stimulated intracellular cGMP levels was blocked by Dupont 753, suggesting signal transduction through ANG II receptors of the AT1 class. ANP (10(-7) M) for 24 h completely abolished the ANG II-induced proliferation in MMC. However, 10(-7) M ANP had no significant effect on mitogenesis induced by platelet-derived growth factor or epidermal growth factor. Furthermore, ANP reduced the ANG II-stimulated expression of the proliferating cell nuclear antigen, a cofactor of polymerase delta that is active in the S-phase of the cell cycle. The addition of 10(-3) M N-monobutyryl-guanosine 3':5'-cyclic monophosphate or 8-bromo-guanosine 3':5'-cyclic monophosphate also blocked the ANG II-induced proliferation. ANP (10(-7)) M for 24 h had no significant influence on the expression (number and dissociation constant) of ANG II receptors as determined by binding assays. These results suggest that, besides the previously shown vasoconstrictive and vasodilating effects, complex interactions between ANG II and ANP exist that can modulate mesangial cell growth.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Angiotensin II-induced proliferation of cultured murine mesangial cells: inhibitory role of atrial natriuretic peptide. 136 89

Our previous study has shown that angiotensin II induces the rapid tyrosine phosphorylation and activation of phospholipase C-gamma 1 in cultured rat aortic smooth muscle (RASM) cells (Marrero, M.B., Paxton, W.G., Duff, J. L., Berk, B. C., and Bernstein, K. E. (1994) J. Biol. Chem, 269, 10935-10939). This signaling pathway is initiated by ligand binding to the AT1 receptor, a cell surface G protein-coupled receptor. Antibodies to pp60c-src were introduced into RASM cells by electroporation. Angiotensin II-stimulated tyrosine phosphorylation of phospholipase C-gamma 1 was eliminated by the anti-pp60c-src antibodies but not by anti-mouse IgG or bovine serum albumin. Angiotensin II also induced the rapid tyrosine phosphorylation of pp120, a known pp60c-src kinase substrate, and this phosphorylation was also specifically inhibited by anti-pp60c-src antibodies. Electroporation of RASM cells with anti-pp60c-src antibodies had no effect on platelet-derived growth factor-stimulated tyrosine phosphorylation of PLC-gamma 1. Anti-pp60c-src also reduced the angiotensin II-stimulated inositol 1,4,5-trisphosphate production by 78%, while it had no effect on the platelet-derived growth factor-stimulated inositol 1,4,5-trisphosphate production. These data provide the first evidence for a direct involvement of pp60c-src kinase in angiotensin II-mediated PLC-gamma 1 phosphorylation and activation. Furthermore, it also describes a pathway in which a seven-transmembrane receptor can stimulate an intracellular tyrosine kinase.
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PMID:Electroporation of pp60c-src antibodies inhibits the angiotensin II activation of phospholipase C-gamma 1 in rat aortic smooth muscle cells. 754 Oct 47

Several experimental studies point to a potential role of angiotensin II (Ang II) in the progression of glomerulosclerosis even in the absence of glomerular hypertension. We tested the hypothesis that Ang II acts as a growth factor for adult human mesangial cells (AHMC). AHMC were isolated from noninvolved parts of tumor nephrectomy specimens and grown in RPMI medium with the addition of fetal calf serum (FCS). All studies were performed with growth-arrested cells. Proliferation studies were done in serum-free standard growth medium (SF) with the addition of either various concentrations of insulin, plasma-derived serum, or FCS. Ang II (10(-10) to 10(-6) M) dose dependently increased the 3H-thymidine uptake of AHMC up to 57 +/- 13% over solvent controls (p < 0.01). In parallel, the DNA content was 36 +/- 10% higher (p < 0.05) than in solvent controls after 2 days of culture. The cell numbers were higher up to 47 +/- 8% in Ang II (10(-6) M) stimulated cultures after 4 days of incubation (p < 0.01). The effect of Ang II was specific, since it was almost completely obliterated by the AT1 receptor antagonist DuP753. The effect of Ang II was particularly marked when cultures were incubated with SF plus high concentrations (1.7 x 10(-6) M) of insulin or SF plus 10% plasma-derived serum. In contrast, the effect was not significant when cultures were incubated with SF plus 10% FCS. Ang II, when added to platelet-derived growth factor at various concentrations, did not further increase the proliferation. The effect on protein synthesis was assessed in growth-arrested AHMC by 3H-methionine uptake and protein/DNA ratio in cell lysates. Ang II (10(-10) to 10(-6) M) dose dependently increased the 3H-methionine uptake of AHMC up to 47 +/- 10% over solvent controls (p < 0.01). In parallel Ang II (10(-8) to 10(-6) M) dose dependently increased the 3H-methionine uptake of the protein/DNA ratio by 24 +/- 6% after 48 h of incubation. DuP753 obliterated the stimulatory effect of Ang II. Ang II (10(-6) M) also increased the mRNA of the immediate-early growth-related gene Egr-1. We conclude that Ang II induces hypertrophy and proliferation in adult human mesangial cells. This result is of interest with respect to a potential role of Ang II in the pathogenesis of glomerulosclerosis in humans.
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PMID:Angiotensin II induces hypertrophy and hyperplasia in adult human mesangial cells. 771 40

Angiotensin (ANG) II has been previously shown to stimulate proliferation of neonatal rat cardiac fibroblasts via AT1 receptors. Here we conducted studies to assess involvement in this process of two second messengers linked to AT1 receptors, protein kinase C (PKC) and Ca2+. Several findings argue against a dominant role for PKC in ANG II-induced mitogenesis: 1) [Sar1]ANG II, which produced a modest, transient increase in PKC activity, was equally effective in inducing thymidine incorporation into DNA in PKC-depleted cells, whereas the effect of platelet-derived growth factor (PDGF)-BB on thymidine incorporation was reduced to the level observed with [Sar1]ANG II; 2) phorbol 12-myristate 13-acetate (PMA), a potent PKC stimulator, was ineffective in stimulating thymidine incorporation; and 3) PKC downregulation or the highly specific PKC inhibitor, compound 3, eliminated PMA-induced mitogen-activated protein (MAP) kinase activity but did not affect comparable increases induced by [Sar1]ANG II or PDGF-BB. Increased intracellular Ca2+ may be sufficient to account for [Sar1]ANG II-induced MAP kinase activity because ionomycin also increased MAP kinase activity and chelation of intracellular Ca2+ eliminated [Sar1]ANG II-induced activity in PKC-depleted fibroblasts. However, Ca2+ chelation did not prevent [Sar1]ANG II-induced MAP kinase activity in non-PKC-depleted fibroblasts. Thus ANG II can activate MAP kinase in cardiac fibroblasts by either Ca(2+)- or PKC-dependent pathways, and whereas the full effect of PDGF-BB on thymidine incorporation and cell proliferation requires a phorbol ester-sensitive PKC, the hyperplastic growth effect of ANG II does not.
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PMID:Involvement of protein kianse C and Ca2+ in angiotensin II-induced mitogenesis of cardiac fibroblasts. 797 94

Cell proliferation influences the expression of numerous tissue-specific genes. The angiotensin AT1 receptor is highly expressed on vascular smooth muscle cells where it mediates cell contraction upon activation with angiotensin II. Since vascular smooth muscle cell de-differentiation leads to differential expression of several genes, we investigated the effects of cell growth on angiotensin AT1 receptor gene expression in vascular smooth muscle cells in culture. Northern hybridization analysis revealed a decrease of angiotensin AT1 receptor mRNA levels to approximately 20% in proliferating cells in comparison to growth-arrested cells. There is a correlative loss of membrane-associated angiotensin AT1 receptor protein in growing cells versus non-growing cells, as assessed by saturation radioligand binding assays. In addition, the BB-isoform of platelet-derived growth factor (PDGF-BB), which induces proliferation of quiescent vascular smooth muscle cells, causes a marked down-regulation of angiotensin AT1 receptor mRNA. These data suggest that proliferation of vascular smooth muscle cells leads to reduced angiotensin AT1 receptor gene expression. The mechanisms underlying this process and its physiological implications remain to be defined.
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PMID:Regulation of angiotensin AT1 receptor gene expression during cell growth of vascular smooth muscle cells. 866 64

In addition to its vasoconstrictor and aldosterone-stimulating action, angiotensin II also drives cell growth and replication in the cardiovascular system, which may result in myocardial hypertrophy and hypertrophy or hyperplasia of conduit and resistance vessels in certain subjects. These actions are mediated through angiotensin II receptors (subtype AT1), which activate the G protein, phospholipase C, diacylglycerol and inositol trisphosphate pathway, to increase the expression of certain protooncogenes (c-fos, c-myc and c-jun) and growth factors (platelet-derived growth factor-A-chain, transforming growth factor-beta 1 and basic fibroblast growth factor). The cellular responses to angiotensin II in vascular smooth muscle have been shown in different hypertensive vessels to be either hypertrophy alone, hypertrophy and DNA synthesis without cell division (polyploidy) or DNA synthesis with cell division (hyperplasia). In genetic hypertension, the altered structure of small arteries is due to either cellular hyperplasia or remodeling, whereas in renovascular hypertension there is hypertrophy of vascular smooth muscle cells. Angiotensin II also increases synthesis of some matrix components, activates blood monocytes and is thrombogenic. Angiotensin-converting enzyme (ACE) inhibitors prevent or reverse vascular hypertrophy in animal models of hypertension; this seems to be a class effect, shared to some extent with calcium channel blocking agents. In human hypertension, ACE inhibitors reduce the increased media/lumen ratio of large and small arteries in hypertension and increase arterial compliance. These properties are also shared by losartan, the first of the new class of angiotensin II receptor (AT1) antagonists. The clinical implications of these findings need to be tested through rigorous and prospective clinical trials.
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PMID:The renin-angiotensin system and vascular hypertrophy. 883 52

Angiotensin II is vasoconstrictor and antinatriuretic; it also stimulates cell growth and proliferation in vascular smooth muscle, resulting in hypertrophy or hyperplasia of conduit and resistance vessels. These actions are mediated through angiotensin II receptors (AT1 subtype), which activate several G-protein-dependent intracellular transduction pathways, such as the phospholipase C, diacylglycerol and inositol trisphosphate the mitogen-activated protein (MAP) kinase pathway, and Janus kinase (JAK)-signal transducers and activators of the transcription (STAT)-mediated pathway. These can all increase the expression of certain proto-oncogenes, particularly c-fos. Angiotensin II also stimulates the activity of certain growth factors, such as platelet-derived growth factor-A-chain and basic fibroblast growth factor. The cellular responses to angiotensin II in vascular smooth muscle have been shown in different hypertensive vessels to be either hypertrophy alone, hypertrophy and DNA synthesis without cell division (polyploidy), or DNA synthesis with cell division (hyperplasia). In genetic hypertension, there is either cellular hyperplasia or remodeling, whereas in renovascular hypertension, there is hypertrophy of vascular smooth muscle cells. Angiotensin-converting enzyme (ACE) inhibitors prevent or reverse vascular hypertrophy in animal models of hypertension. In human hypertension, ACE inhibitors reduce the increased media/lumen ratio of large and small arteries and increase arterial compliance. These properties are also shared by AT1 receptor antagonists. The implications of these findings for morbidity and mortality in hypertension still await rigorous testing in prospective clinical trials.
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PMID:Vascular hypertrophy in hypertension: role of the renin-angiotensin system. 952 May 14

The interaction of ANG II with platelet-derived growth factor (PDGF)-BB-induced DNA synthesis was studied in cultured rat aortic smooth muscle cells. PDGF-BB-induced DNA synthesis was delayed (approximately 6-8 h) by ANG II as shown by a time-course experiment. Losartan, an AT1-receptor antagonist, blocked the transient inhibitory effect of ANG II, whereas the AT2-receptor antagonist PD-123319 had no effect. Autocrine- or paracrine-acting transforming growth factor-beta 1 (TGF-beta 1), believed to be a mediator of ANG II-induced inhibitory effects, was not responsible for the delay of PDGF-BB-induced DNA synthesis, because a potent TGF-beta 1 neutralizing antibody could not reverse this effect of ANG II, nor was the delay of the PDGF-BB effect caused by inhibition of PDGF-beta-receptor phosphorylation as shown by Western blot analysis of immunoprecipitated PDGF-beta receptor. In conclusion, our results show that ANG II can exert a transient inhibitory effect on PDGF-BB-induced proliferation via the AT1 receptor.
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PMID:PDGF-BB-induced DNA synthesis is delayed by angiotensin II in vascular smooth muscle cells. 961 86

The accumulation and organization of extracellular matrix (ECM) components play critical roles in development, maintenance, and pathogenesis of most organ systems. These processes are regulated by the precisely orchestrated expression of ECM components, their receptors, and matrix proteases. The collagen gel culture system has been extensively used as a model to examine ECM remodeling similar to that which occurs during development and wound healing. Growth factors, including transforming growth factor-beta, platelet-derived growth factor, insulin-like growth factor, and angiotensin II, have been shown to stimulate collagen gel contraction. The present studies were undertaken to begin to examine the mechanisms through which angiotensin II stimulates collagen remodeling and gel contraction. These studies indicate that angiotensin II stimulates collagen gel contraction by isolated heart fibroblasts in a dose-dependent manner and that this response is inhibited by the AT1 receptor antagonist Losartan. Furthermore, stimulation of collagen gel contraction by angiotensin II is also blocked by the src-related tyrosine kinase inhibitors genistein and herbimycin, indicating that activation of tyrosine kinases plays critical roles in this process. Stimulation of gel contraction by angiotensin II also involves the activation of JAK2, a member of the JAK/STAT pathways of transcriptional activation. Immunoprecipitation of surface-labeled fibroblasts indicate that cell surface levels of collagen-binding integrins also increase in response to angiotensin II treatment. Determining the underlying mechanisms regulating ECM remodeling is essential to understanding the role of ECM organization in development and disease.
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PMID:Angiotensin II-stimulated collagen gel contraction by heart fibroblasts: role of the AT1 receptor and tyrosine kinase activity. 976 19

Angiotensin II acts on the cardiac fibroblast to produce a mitogenic response. Nitric oxide and N-acetylcysteine have been used to determine if oxidative stress influenced the effects of angiotensin II on the cardiac fibroblast. Angiotensin II activated the mitogen-activated protein kinases designated extracellular signal-regulated kinases within 5 min by interacting with the AT1 receptor. This activation was completely independent of protein kinase C and was inhibited when farnesylation was blocked, implicating Ras involvement. Pretreatment of cardiac fibroblasts with either N-acetylcysteine for 8 h or nitric oxide for 10 min suppressed this activation by angiotensin II in a dose-dependent manner. However, when both agents were added, inhibition was essentially complete. This combined effect of N-acetylcysteine and nitric oxide to block ERKs activation also was found if the activity was stimulated by either another growth factor (platelet-derived growth factor) or by the addition of phorbol ester, suggesting the effect was not limited to the receptor site alone. The results are consistent with the hypothesis that hormonal activation of mitogenic steps such as ERKs is influenced by increased oxidative stress, which is reduced by the combined effects of N-acetylcysteine and nitric oxide.
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PMID:Nitric oxide and N-acetylcysteine inhibit the activation of mitogen-activated protein kinases by angiotensin II in rat cardiac fibroblasts. 983 56


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