Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.6 (RNA polymerase)
34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin II (Ang II), a vasoactive octapeptide, has been implicated in cardiac growth and the development of hypertrophy and fibrosis secondary in hypertensive disease. These consequences of Ang II imply an effect on the function and morphology of cardiac interstitial cells (fibroblasts). The present investigation was designed to (1) determine whether neonatal heart fibroblasts (NHFs) possess functional Ang II receptors on their plasma membrane and (2) examine the effects of Ang II on NHFs in vitro using three- and two-dimensional (3D and 2D, respectively) cultures. Several analytic techniques were used to test the specific questions of the present study. Since cardiac fibroblast phenotype can be influenced by culture conditions, both 2D and 3D cultures were used in the present investigations. Reverse-transcriptase polymerase chain reaction and radioligand binding analysis were used to test for the presence of Ang II receptors on NHFs. Both revealed that NHFs in 2D culture possess Ang II receptor mRNA and Ang II receptors. When isolated NHFs were cultured in 3D collagen gels and treated with Ang II, gel contraction was stimulated by NHFs. This effect was attenuated by the specific Ang II receptor antagonist [Sar1,Ala8]Ang II. Ang II-stimulated gel contraction was completely inhibited by extracellular matrix receptor (beta 1-integrin) antibodies (P < .05), supporting previous studies indicating that collagen gel contraction is mediated via the integrins. Immunofluorescent staining was used to test the localization of cell-surface integrins. A more intense staining pattern for beta 1-integrin in Ang II-treated versus control cells was observed.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Integrin-mediated collagen gel contraction by cardiac fibroblasts. Effects of angiotensin II. 829 68

Angiotensin II (Ang II) stimulates pathologic myocardial fibrosis. Cardiac fibroblasts (CFb) and myofibroblasts mediate this response, perhaps in part by indirect production of specific cytokines. We sought to determine if Ang II could stimulate transforming growth factor-beta1 (TGF-beta1) gene expression and protein production in adult rat CFb and two cardiac myofibroblast cell types, scar myofibroblasts (MyoFb) and valvular interstitial cells (VIC). Confluent CFb, MyoFb, and VIC in serum-deprived (0.4% FCS) media were treated with Ang II (10(-7) m for CFb; 10(-9) m for MyoFb, VIC) for 24 h. Untreated cells served as controls. Culture media was collected and TGF-beta1 levels determined in triplicate using a sandwich ELISA. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis was performed to determine TGF-beta1 mRNA expression. Ang II increased CFb (P<0.02) and VIC (P<0.04) TGF-beta1 mRNA expression, while the increase in MyoFb was not statistically significant. MyoFb produced the highest TGF-beta1 levels under control conditions compared to VIC and CFb. Ang II stimulated further TGF-beta1 secretion in VIC and CFb, but not MyoFb. The AT1 receptor antagonist Losartan (10(-7) m) greatly attenuated Ang II-stimulated TGF-B1 secretion and decreased TGF-beta1 immunostaining in VIC. The AT2 receptor antagonist PD123177 (10(-7) m) also decreased secretion and immunostaining of TGF-beta1 in VIC, but to a lesser extent than Losartan. TGF-beta1 secretion by MyoFb was unaffected by Losartan and PD123177, although TGF-B1 immunostaining was absent or greatly decreased, respectively, compared to Ang II-treated MyoFb. Ang II stimulates TGF-beta1 gene expression and/or protein production in cardiac fibroblast-like cells which may act as an autocrine/paracrine stimulus to collagen formation. Furthermore, TGF-beta1 production and secretion in these cells can be modulated by specific Ang II receptor antagonists, suggesting a potential benefit in preventing/attenuating pathologic myocardial fibrosis.
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PMID:Angiotensin II stimulated expression of transforming growth factor-beta1 in cardiac fibroblasts and myofibroblasts. 923 48

Angiotensin II (Ang II) has powerful modulatory actions on cardiovascular function that are mediated by specific receptors located on neurons within the hypothalamus and brain stem. Incubation of neuronal cocultures of rat hypothalamus and brain stem with Ang II elicits an Ang II type 1 (AT1) receptor-mediated inhibition of total outward K+ current that contributes to an increase in neuronal firing rate. However, the exact K+ conductance(s) that is inhibited by Ang II are not established. Pharmacological manipulation of total neuronal outward K+ current revealed a component of K+ current sensitive to quinine, tetraethylammonium, and 4-aminopyridine, with IC50 values of 21.7 micromol/L, 1.49 mmol/L, and 890 micromol/L, respectively, and insensitive to alpha-dendrotoxin (100 to 500 nmol/L), charybdotoxin (100 to 500 nmol/L), and mast cell degranulating peptide (1 micromol/L). Collectively, these data suggest the presence of Kv2.2 and Kv3.1b. Biophysical examination of the quinine-sensitive neuronal K+ current demonstrated a macroscopic conductance with similar biophysical properties to those of Kv2.2 and Kv3.1b. Ang II (100 nmol/L), in the presence of the AT2 receptor blocker PD123,319, elicited an inhibition of neuronal K+ current that was abolished by quinine (50 micromol/L). Reverse transcriptase-polymerase chain reaction analysis confirmed the presence of Kv2.2 and Kv3.1b mRNA in these neurons. However, Western blot analyses demonstrated that only Kv2.2 protein was present. Coexpression of Kv2.2 and the AT1 receptor in Xenopus oocytes demonstrated an Ang II-induced inhibition of Kv2.2 current. Therefore, these data suggest that inhibition of Kv2.2 contributes to the AT1 receptor-mediated reduction of neuronal K+ current and subsequently to the modulation of cardiovascular function.
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PMID:Angiotensin II type 1 receptor-mediated inhibition of K+ channel subunit kv2.2 in brain stem and hypothalamic neurons. 1002 10

Bone marrow endothelial cells are the essential component of the bone marrow microenvironment. They produce many kinds of cytokines, including stimulators and inhibitors. Many researchers have suggested that in the presence of endothelial cell layer, CD34+CD38- cells are capable of expansion. The ability of the endothelial cell layer to protect hematopoietic stem cells from extensive differentiation may be related to the inhibitors derived from endothelial cells. The aim of the present study was to determine whether the inhibitors thymosin beta4 and AcSDKP are elaborated by murine bone marrow endothelial cells. Murine bone marrow endothelial cells (mBMECs) were cultured in serum-free conditioned medium. Reverse transcriptase polymerase chain reaction (RT-PCR) was used to analyze the differential expression of the thymosin-beta gene, and reverse phase high-performance chromatography (HPLC) and mass spectroscopy were used to determine the concentration of thymosin beta4 (Tbeta4) and AcSDKP in EC lysate and in the medium (mBMEC-CM). Colony-forming unit granulocyte-macrophage (CFU-GM) colony assays were used to examine the effect of components (mw 3-10 kD, <3 kD) of mBMEC-CM, thymosin beta4, and AcSDKP on the proliferation of hematopoietic cells.mBMECs expressed Tbeta4 mRNA. In EC lysate and mBMEC-CM, Tbeta4 and AcSDKP were detected. After adding protease inhibitors, the concentration of Tbeta4 in EC lysate increased significantly, while the concentration of AcSDKP decreased. mBMEC-CM (mw 3-10 kD) had no effect on the formation of CFU-GM. However, mBMEC-CM (mw <3 kD) could inhibit the growth of CFU-GM. Tbeta4 (10(-11) approximately 10(-7)mol/L) and AcSDKP (10(-11) approximately 10(-5)mol/L) had dose-dependent inhibitory effects on the growth of CFU-GM. Angiotensin converting enzyme (ACE), the enzyme degrading AcSDKP, could partially eliminate the inhibitory effect of mBMEC-CM (mw <3 kD) on CFU-GM.BMECs express and secrete Tbeta4 and AcSDKP. Tbeta4 exists in the 3-10 kD component of mBMEC-CM, while AcSDKP exists in the <3 kD component of ECCM. Both components exert inhibitory effects on the proliferation of hematopoietic progenitors.
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PMID:Bone marrow endothelial cells secrete thymosin beta4 and AcSDKP. 1116 1

Angiotensin II (Ang II) AT(1A) receptors are localized to renomedullary interstitial cells (RMIC) in the inner stripe of the outer medulla but not in the inner medulla. Thus, there seems to be a correlation between decreases in AT(1A) receptor binding to RMIC and increases in interstitial osmolality, suggesting that osmolality is important in determining Ang II binding to RMIC. Cultured RMIC were incubated in media of differing osmolalities (330, 630, 930, and 1230 mOsm/kg H(2)O). (125)I-[Sar(1), Ile(8)] Ang II binding to AT(1A) receptors on RMIC grown in hyperosmolal media (930 mOsm/kg H(2)O) was reduced compared with isoosmolal (330 mOsm/kg H(2)O) media and was progressively reduced with further increases of osmolality. Similar studies were performed using bradykinin (BK) as a control peptide. Binding of the BK receptor ligand (125)I-[HPP-Hoe 140] to B(2) receptors was not affected by varying osmolality of the media. Reverse transcriptase-PCR demonstrated the presence of the mRNA expression for both AT(1A) and B(2) receptors at each osmolality. The conclusion is that osmolality modulates Ang II binding to RMIC; in these cells, this phenomenon is restricted to Ang II as BK binding is not affected. Osmolality-induced changes in Ang II binding may modulate the actions of this peptide on RMIC and provide an important mechanism by which these cells modulate renal medullary function.
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PMID:Angiotensin II binding to renomedullary interstitial cells is regulated by osmolality. 1118 92

Genetic responses that characterize experimental autoimmune myocarditis (EAM) have not yet been determined. To investigate gene expression in the myocardium of EAM, absolute copy numbers of 44 mRNA species [calcium-handling proteins, contractile proteins, natriuretic peptides (NPs), cytokines, chemokines, growth factors, renin-angiotensin-aldosterone (RAA) system, endothelins (ETs) and extracellular matrix] in synthesized cDNA from a fixed quantity of total heart RNA were assessed using real-time reverse-transcriptase PCR at days 0, 14, 21 and 28 after immunization. alpha-Cardiac myosin showed a 26.3-fold decrease and beta-cardiac myosin a 3.75-fold increase at day 14. Atrial NP and brain NP increased 47.7- and 6.35-fold at days 21 and 14 respectively. Angiotensin II type 1 receptor, angiotensin-converting enzyme and ET1 increased 22.3-fold at day 21, 6.30-fold at day 21 and 16.8-fold at day 14 respectively. Aldosterone receptor decreased 2.15-fold at day 14, but aldosterone synthetase was detected only at days 14 and 21. Interleukin (IL)-2, IL-10, interferon-gamma and monocyte chemo-attractant protein-1 increased 9.08-fold at day 14, 398-fold at day 21, 43.1-fold at day 14 and 142-fold at day 14 respectively. Collagen type 3, collagen type 1 and fibronectin increased 34.6-, 1.74- and 44.4-fold respectively at day 21. Interestingly, osteopontin showed a 4540-fold increase and it was the highest mRNA of all at day 14. An isoform of cardiac myosin and NP are dramatically changed in EAM. RAA system and ET expressions are changed differently during the EAM time course. Cytokine, chemokine and extracellular matrix greatly increase and, in particular, large numbers of osteopontin mRNA are expressed in early EAM.
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PMID:Time course of gene expression in rat experimental autoimmune myocarditis. 1244 15

Previous in vivo studies in cardiomyopathic hamsters suggested that the expression of vasopressin (AVP) V2 mRNA is up- regulated by angiotensin II. The present study was performed to determine whether angiotensin II plays a role in regulating the expression of AVP V2 mRNA and aquaporin-2 (AQP2) mRNA in the inner medullary collecting duct (IMCD) of the male Wistar rat. The expression of AVP V2 mRNA and AQP2 mRNA in the IMCD was measured by competitive reverse-transcriptase polymerase chain reaction (RT-PCR). Six groups of experiments were performed. In the first group, we incubated IMCD with 3 different doses of angiotensin II (10(-11), 10(-9) and 10(-7) mol/L). Angiotensin II caused a significant increase in the AVP V2 mRNA in a dose-dependent manner but its effect on AQP2 mRNA was modest. This effect of angiotensin II was inhibited by angiotensin II receptor antagonist, [Sar1,Ile8]-angiotensin II. To examine the role of PKA in mediating an increase in AVP V2 mRNA expression, we incubated IMCD with 10(-7) and 10(-11) M of angiotensin II in the presence of a specific protein kinase A (PKA) inhibitor, Rp diasteroisomer of adenosine 3'-5'-cylic monophosphothionate (Rp-cAMPS). The angiotensin II-induced upregulation of V2 mRNA was abolished. In the fourth group, we examined the effect of protein kinase C (PKC) inhibition on V2 mRNA expression. The upregulation of V2 mRNA induced by angiotensin II was greatly exaggerated when IMCD was incubated with angiotensin II and RO-31-8220 (PKC inhibitor). In the fifth and sixth groups of studies, we determined the direct effect of PKA and PKC on regulating the expression of V2 mRNA and AQP2 mRNA in the IMCD, respectively. Dibutryl cAMP stimulated an upregulation in the expression of V2 mRNA and AQP2 mRNA, whereas phorbol esters suppressed the expression of V2 mRNA. These results suggested that PKA stimulates and PKC suppresses the expression of V2 mRNA in the IMCD of the kidney.
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PMID:Angiotensin II upregulates the expression of vasopressin V2 mRNA in the inner medullary collecting duct of the rat. 1264 65

Angiotensin (Ang) II is now recognized to be a mediator of a wide variety of inflammatory processes. This study investigated renin-angiotensin system (RAS) components and a number of inflammatory mediators in left ventricular biopsies from 2-vessel disease unstable angina (UA) (n=43) and stable angina (SA) (n=15) patients undergoing coronary bypass surgery. Biopsy samples from 6 patients undergoing valve replacement for mitral stenosis served as controls. UA patients were randomly assigned to angiotensin-converting enzyme (ACE)-inhibitor (ramipril), AT1 antagonist (valsartan), or placebo and treated during the 5 days preceding coronary bypass surgery, performed from 6 to 9 days after coronary angiography. During coronary angiography coronary blood flow was measured and samples were obtained from aorta and coronary sinus for determination of Ang I and Ang II gradients. The hearts of UA patients produced Ang II in a greater amount than in SA patients (P<0.01). UA biopsy samples showed numerous DR+ cells, identified as lymphocytes, macrophages, and endothelial cells. Reverse-transcriptase polymerase chain reaction showed overexpression of AGTN, ACE, and AT1-R genes, as well as upregulation of TNF-alpha, IL-6, IFN-gamma, and iNOS genes (P<0.01), with no differences between nonischemic and potentially ischemic areas. AGTN, ACE, and cytokine genes were mainly localized on endothelial cells. Ramipril and valsartan markedly decreased the expression levels of TNF-alpha, IL-6, and iNOS, and, to a lesser extent, of IFN-gamma genes, but did not affect the number of DR+ cells, with no significant difference between the 2 treatments. These results show that locally generated Ang II amplifies the immunomediated inflammatory process of coronary microvessels occurring in unstable angina.
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PMID:Cardiac angiotensin II participates in coronary microvessel inflammation of unstable angina and strengthens the immunomediated component. 1521 17

The renin-angitensin system (RAS) plays an important role as a growth factor in cardiac development. Angiotensin converting enzyme is involved in converting angiotensin I to angiotensin II (Ag-II). The effects of Ag-II are mediated by two primary receptors, type 1 (AT1) and type 2 (AT2). Ag-II stimulates transforming growth factor-beta1(TGF-beta1) and acts as a potent stimulant of myocyte growth and fetal contractile protein gene transcription. The aim of this study was to determine the expression of Ag-II receptor subtypes and TGF-beta1 in the hypoplastic heart of nitrofen-induced congenital diaphragmatic hernia (CDH). CDH was induced in pregnant rats following administration of 100 mg nitrofen on day 9.5. The fetuses were divided into three groups: normal controls (n=16), nitrofen-treated without CDH (n=16), and nitrofen-induced CDH (n=16). Reverse transcriptase-polymerase chain reaction was performed to evaluate mRNA expression of AT1, AT2, and TGF-beta1. Levels of mRNA were expressed as a ratio of the band density divided by that of beta-actin. AT1 and AT2 mRNA expressions were significantly decreased in CDH heart compared with controls (0.43+/-0.33 vs. 1.0+/-0.48 and 0.62+/-0.23 vs. 1.4+/-0.43, respectively). TGF-beta1 mRNA expressions were also significantly decreased in CDH heart compared with controls (0.38+/-0.17 vs. 0.72+/-0.26). No significant difference was found between the hearts of controls and nitrofen-treated rats without CDH. The decreased expression of AT1, AT2, and TGF-beta1 mRNA in the hypoplastic heart suggests that the downregulation of RAS may be involved in the pathogenesis of cardiac hypoplasia in nitrofen-induced CDH.
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PMID:Altered expression of angiotensin II receptor subtypes and transforming growth factor-beta in the heart of nitrofen-induced diaphragmatic hernia in rats. 1557 92

Magnesium modulates vascular smooth muscle cell (VSMC) function. However, molecular mechanisms regulating VSMC Mg2+ remain unknown. Using biochemical, pharmacological, and genetic tools, the role of transient receptor potential membrane melastatin 7 (TRPM7) cation channel in VSMC Mg2+ homeostasis was evaluated. Rat, mouse, and human VSMCs were studied. Reverse transcriptase polymerase chain reaction and immunoblotting demonstrated TRPM7 presence in VSMCs (membrane and cytosol). Angiotensin II (Ang II) and aldosterone increased TRPM7 expression. Gene silencing using small interfering RNA (siRNA) against TRPM7, downregulated TRPM7 (mRNA and protein). Basal [Mg2+]i, measured by mag fura-2AM, was reduced in siRNA-transfected cells (0.39+/-0.01 mmol/L) versus controls (0.54+/-0.01 mmol/L; P<0.01). Extracellular Mg2+ dose-dependently increased [Mg2+]i in control cells (Emax 0.70+/-0.02 mmol/L) and nonsilencing siRNA-transfected cells (Emax 0.71+/-0.04 mmol/L), but not in siRNA-transfected cells (Emax 0.5+/-0.01 mmol/L). The functional significance of TRPM7 was evaluated by assessing [Mg2+]i and growth responses to Ang II in TRPM7 knockdown cells. Acute Ang II stimulation decreased [Mg2+]i in control and TRPM7-deficient cells in a Na+-dependent manner. Chronic stimulation increased [Mg2+]i in control, but not in siRNA-transfected VSMCs. Ang II-induced DNA and protein synthesis, measured by 3[H]-thymidine and 3[H]-leucine incorporation, respectively, were increased in control and nonsilencing cells, but not in TRPM7 knockdown VSMCs. Our data indicate that VSMCs possess membrane-associated, Ang II-, and aldosterone-regulated TRPM7 channels, which play a role in regulating basal [Mg2+]i, transmembrane Mg2+ transport and DNA and protein synthesis. These novel findings identify TRPM7 as a functionally important regulator of Mg2+ homeostasis and growth in VSMCs.
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PMID:Transient receptor potential melastatin 7 ion channels regulate magnesium homeostasis in vascular smooth muscle cells: role of angiotensin II. 1559 Dec 30


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