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Tyrosine kinase inhibition affects type 1 angiotensin II receptor internalization

JOURNAL OF RECEPTOR AND SIGNAL TRANSDUCTION RESEARCH 1999年第6期19卷 975-993页

作者： Becker, BN Kondo, S Chen, JK Harris, RC Vanderbilt Univ Med Ctr Sch Med Dept Med Nashville TN 37232 USA Dept Vet Affairs Med Ctr Nashville TN 37232 USA

Growth factor receptors activate tyrosine kinases and undergo endocytosis. Recent data suggest that tyrosine kinase inhibition can affect growth factor receptor internalization. The type 1 angiotensin II receptor (AT(1)R) which is a G-protein-coupled receptor, also activates tyrosine kinases and undergoes endocytosis. Thus, we examined whether tyrosine kinase inhibition affected AT(1)R internalization. To verify protein tyrosine phosphorylation, both LLCPKCl4 cells expressing rabbit AT(1)R (LLCPKAT1R) and cultured rat mesangial cells (MSC) were treated with angiotensin II (Ang II) [1-100 nM] then solubilized and immunoprecipitated with antiphosphotyrosine antisera. Immunoblots of these samples demonstrated that Ang II stimulated protein tyrosine phosphorylation in both cell types. Losartan [1 mu M], an AT(1)R antagonist, inhibited Ang II-stimulated protein tyrosine phosphorylation, LLCPKAT1R cells displayed specific I-125-Ang 11 binding at apical (AP) and basolateral (BL) membranes, and both AP and BL AT(1)R activated tyrosine phosphorylation. LLCPKAT1R cells, incubated with genistein (Gen) [200 mu M] or tyrphostin B-48 (TB-48) [50 mu M], were assayed for acid-resistant specific I-125-Ang II binding, a measure of Ang TI internalization. Both Gen (n=7) and TB-48 (n=3) inhibited AP I-125-Ang II internalization (80 +/- 7% inhibition;p < 0.025 vs. control). Neither compound affected BL internalization. TB-1, a non-tyrosine kinase-inhibiting tyrphostin, did not affect AP I-125-Ang 11 endocytosis (n=3), suggesting that the TB-48 effect was specific for tyrosine kinase inhibition. Incubating MSC with Gen (n=5) or herbimycin A [150 ng/ml] (n=4) also inhibited MSC I-125-Ang II internalization (82 +/- 11% inhibition;p<0.005 vs. control). Thus, tyrosine kinase inhibition prevented Ang IT internalization in MSC and selectively decreased AP Ang II internalization in LLCPKAT1R cells suggesting that AP AT(1)R in LLCPKATIR cells and MSC AT(1)R have similar endocytic phenotypes, and

关键词：血管紧张素ⅱ/代谢酶抑制剂/药理学染料木黄酮/药理学肾小球膜/代谢蛋白酪氨酸激酶类/拮抗剂和抑制剂受体血管紧张素/代谢信号传导/药物作用酪氨酸磷酸化抑制剂/药理学动物兔大鼠

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OVERALL CARDIOVASCULAR REGULATION

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ANNUAL REVIEW OF PHYSIOLOGY 1976年第1期38卷 537-570页

作者： OBERG, B VET SCH UPPSALA DEPT PHYSIOL UPPSALA 7 SWEDEN

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No expression of angiotensin II receptors and angiotensin-converting enzyme in myxomatous canine mitral valve leaflets. An autoradiographic study

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JOURNAL OF VETERINARY MEDICINE SERIES A-PHYSIOLOGY PATHOLOGY CLINICAL MEDICINE 1999年第8期46卷 465-472页

作者： Mow, T Pedersen, HD Royal Vet & Agr Univ Dept Anat & Physiol DK-1870 Frederiksberg C Denmark Royal Vet & Agr Univ Small Anim Hosp Dept Clin Sci Frederiksberg Denmark

The renin-angiotensin system, including angiotensin (Ang) II and angiotensin-converting enzyme (ACE), plays an important role in cardiac fibrous tissue formation. Since changes in valvular collagen are a central part of myxomatous mitral valve disease in the dog, we speculated that Ang II and ACE might pla! a role in the pathogenesis of this disease. In 10 mitral valves, five with and five without clear myxomatous changes, thr presence and distribution of Ang II receptors and ACE was examined autoradiographically, using I-125-Ang II and I-125-lisinopril, respectively. At postmortem examination, diseased valves were taken from old dogs, control valves from young adult dogs. No significant level of Ang II and lisinopril binding was found in normal as well as diseased valve leaflets. Equally low, insignificant levels of I-125-Ang II binding were found in the myocardium of dogs with and without valvular disease. No significant level of myocardial I-125-lisinopril binding was found. The lack of autoradiographic evidence of Ang II receptors and ACF, in normal and diseased canine mitral valve leaflets suggests that the renin-angiotensin system does not play a major role in the pathogenesis of the valvular changes.

关键词：血管紧张素ⅱ/代谢放射自显影术狗疾病/代谢心脏肿瘤/代谢心脏肿瘤/兽医学碘放射性同位素二尖瓣/代谢心肌/代谢黏液瘤/代谢黏液瘤/兽医学肽基二肽酶A/分析受体血管紧张素/分析参考值动物狗

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Angiotensin II induces connective tissue growth factor gene expression via calcineurin-dependent pathways

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AMERICAN JOURNAL OF PATHOLOGY 2003年第1期163卷 355-366页

作者： Finckenberg, P Inkinen, K Ahonen, J Merasto, S Louhelainen, M Vapaatalo, H Müller, D Ganten, D Luft, F Mervaala, E Univ Helsinki Inst Biomed FIN-00014 Helsinki Finland Univ Helsinki Hosp Res Lab FIN-00014 Helsinki Finland Humboldt Univ Fac Med Charite Franz Volhard Clin HELIOS Klinikum Berlin D-10098 Berlin Germany Max Delbruck Ctr Mol Med Berlin Germany

Connective tissue growth factor (CTGF) is a polypeptide implicated in the extracellular matrix synthesis. Previous studies have provided evidence that angiotensin II (Ang II) promotes collagen synthesis and regulates collage a degradation. We investigated whether or not CTGF mediates the profibrotic effects of Ang H in the heart and kidneys and the role of calcineurin-dependent pathways in CTGF gene regulation. In transgenic rats harboring human renin and angiotensinogen genes, Ang H induced an age-dependent increase in myocardial CTGF expression, which was 3.5-fold greater compared to normotensive Sprague Dawley (SD) rats. C-TGF overexpression correlated closely with the Ang H-induced rise in blood pressure. CTGF mRNA and protein were located predominantly in areas with leukocyte infiltration, myocardial, and vascular lesions and co-localized with TGFbeta(1), collagen I, and collagen III mRNA expressions. Ang II induced CTGF mRNA and protein to a lesser extent in the kidneys, predominantly in glomeruli, arterioles, and in the interstitium with ample inflammation. However, no expression was found in the right ventricle or pulmonary arteries. Blockade of calcineurin activity by cyclosporine A completely normalized Ang II-induced CTGF overexpression in heart and kidney, suppressed the inflammatory response, and mitigated Ang H-induced cell proliferation and apoptosis. in contrast, blockade of mTOR (target of rapamycin) pathway by everolimus, further increased the expression of CTGF even though everolimus ameliorated cell proliferation and T-cell-mediated inflammation. Our findings provide evidence that CTGF mediates Ang H-induced fibrosis in the heart and kidneys via blood pressure and calcineurin-dependent pathways.

关键词：血管紧张素Ⅱ/遗传学血管紧张素ⅱ/代谢血压钙神经素/代谢胶原Ⅰ型/遗传学胶原Ⅰ型/代谢胶原Ⅲ型/遗传学胶原Ⅲ型/代谢环孢菌素/代谢基因表达调控心脏/解剖学和组织学即早蛋白质类/遗传学即早蛋白质类/代谢免疫抑制剂/代谢原位杂交胞间信号肽类和蛋白质类/遗传学胞间信号肽类和蛋白质类/代谢肾/解剖学和组织学肾/病理学生物基因修饰大鼠 Sprague-Dawley 肾素/遗传学肾素/代谢西罗莫司/类似物和衍生物西罗莫司/代谢转化生长因子β/遗传学转化生长因子β/代谢转化生长因子β1 动物人类男(雄)性大鼠

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Placental aminopeptidase A as a possible barrier of angiotensin II between mother and fetus

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PLACENTA 2000年第7期21卷 621-627页

作者： Hariyama, Y Itakura, A Okamura, M Ito, M Murata, Y Nagasaka, T Nakazato, H Mizutani, S Nagoya Univ Hosp Matern & Perinatal Care Ctr Dept Matern Showa Ku Nagoya Aichi 4668550 Japan Nagoya Univ Sch Med Dept Obstet & Gynecol Showa Ku Nagoya Aichi 4668550 Japan Nagoya Univ Hosp Div Pathol Clin Lab Showa Ku Nagoya Aichi 4668550 Japan

Aminopeptidase A (AP-A EC 3.4.11.7), which is a membrane-bound zinc metalloprotease, is present in the placenta. AP-A selectively hydrolyzes N-terminal glutamyl and aspartyl residues and cleaves angiotensin II to form angiotensin III. To determine the role of placental aminopeptidase A under physiological and pathological conditions, we evaluated its immunolocalization and enzymatic activities in the placenta. AP-A was localized in the basal zone of the syncytiotrophoblast, in the membranes of the cytotrophoblast, and in fetal arterioles and venules within the stem villi. AP-A activity in the microsomal fraction of placental villi seemed to be remained essentially constant throughout gestation. The renin-angiotensin system is considered to be accelerated in pre-eclampsia. This AP-A activity was higher in pre-eclampsia (2.86 +/- 0.30 nmol beta NA/mg protein/h) than in uncomplicated pregnancy from 28 to 41 weeks of gestation (2.08 +/- 0.18 nmol beta NA/mg protein/h). Angiotensin II evoked AP-A activity in first trimester trophoblast, and Losartan and PD 123177 in combination significantly inhibited this induction of AP-A activity. The results of immunohistochemical evaluation and enzymatic activity suggested that placental aminopeptidase A may play a role as a component of the barrier of angiotensin II between mother and fetus. (C) 2000 Harcourt Publishers Ltd.

关键词：氨肽酶类/分析氨肽酶类/代谢血管紧张素ⅱ/代谢血管紧张素Ⅲ/代谢小动脉/酶学细胞培养的胎儿/血液供给孕龄谷氨酰氨肽酶胎盘/酶学先兆子痫/酶学肾素-血管紧张素系统/生理学组织分布滋养层/酶学小静脉/酶学成年人女(雌)性人类妊娠

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Interplanetary travel and permanent injury to normal heart

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ACTA ASTRONAUTICA 1997年第10期40卷 719-722页

作者： Rowe, WJ 12548 W. Bancroft Swanton Ohio 43558 USA

This hypothesis is that some crewmen on prolonged space flights may develop permanent myocardial injury despite the absence of coronary atherosclerosis and even without the hazards of radiation beyond orbit. This may result from atrophy of skeletal muscle and bone resulting in magnesium ion deficiency predisposing to a vicious cycle with catecholamine elevations, with the latter aggravated by stress, dehydration-provoked angiotensin elevations, unremitting endurance exercise, and in turn a second vicious cycle with severe ischemia. Toxic free radicals can develop complicating ischemia and potential high radiation, with magnesium ion deficiency and high vascular catecholamines playing contributing roles. These free radicals may lead to inactivation of endothelium-derived relaxing factor (EDRF) causing coronary endothelial injury by a third vicious cycle, increased peripheral resistance and coronary vasospasm intensifying ischemia. Local and systemic thrombogenesis could contribute ultimately to focal fibrosis of the myocardium, if the ischemia is not recognized. Sufficient magnesium and time for repair are vital. (C) 1998 Elsevier Science Ltd. All rights reserved.

关键词：航天医学血管紧张素ⅱ/代谢宇航员儿茶酚胺类/代谢运动疗法/方法自由基/代谢镁/代谢镁缺乏心肌缺血/病因学心肌缺血/病理生理学心肌缺血/预防和控制心肌/病理学一氧化氮/代谢人员选用身体耐力/生理学宇宙飞行抗失重措施动物人类

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Tasosartan, enoltasosartan, and angiotensin II receptor blockade: The confounding role of protein binding

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第2期295卷 649-654页

作者： Maillard, MP Rossat, J Brunner, HR Burnier, M Univ Lausanne Hosp Div Hypertens & Vasc Med Lausanne Switzerland

Tasosartan is a long-acting angiotensin II (AngII) receptor blocker. Its long duration of action has been attributed to its active metabolite enoltasosartan. In this study we evaluated the relative contribution of tasosartan and enoltasosartan to the overall pharmacological effect of tasosartan. AngII receptor blockade effect of single doses of tasosartan (100 mg p.o. and 50 mg i.v) and enoltasosartan (2.5 mg i.v.) were compared in 12 healthy subjects in a randomized, double blind, three-period crossover study using two approaches: the in vivo blood pressure response to exogenous AngII and an ex vivo AngII radioreceptor assay. Tasosartan induced a rapid and sustained blockade of AngII subtype-1 (AT1) receptors. In vivo, tasosartan (p.o. or i.v.) blocked by 80% AT1 receptors 1 to 2 h after drug administration and still had a 40% effect at 32 h. In vitro, the blockade was estimated to be 90% at 2 h and 20% at 32 h. In contrast, the blockade induced by enoltasosartan was markedly delayed and hardly reached 60 to 70% despite the i.v. administration and high plasma levels. In vitro, the AT1 antagonistic effect of enoltasosartan was markedly influenced by the presence of plasma proteins, leading to a decrease in its affinity for the receptor and a slower receptor association rate. The early effect of tasosartan is due mainly to tasosartan itself with little if any contribution of enoltasosartan. The antagonistic effect of enoltasosartan appears later. The delayed in vivo blockade effect observed for enoltasosartan appears to be due to a high and tight protein binding and a slow dissociation process from the carrier.

关键词：投药口服血管紧张素Ⅱ/拮抗剂和抑制剂血管紧张素ⅱ/代谢血管紧张素Ⅱ/药理学血压/药物作用血蛋白质类/代谢交叉研究双盲法药物相互作用注射静脉内蛋白质结合嘧啶类/血液嘧啶类/药代动力学嘧啶类/药理学受体血管紧张素 1型受体血管紧张素 2型受体血管紧张素/拮抗剂和抑制剂受体血管紧张素/代谢四唑类/血液四唑类/药代动力学四唑类/药理学成年人人类男(雄)性

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Effects of BAY 10-6734 (Embusartan), a new angiotensin II type I receptor antagonist, on vascular smooth muscle cell growth

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第1期289卷 181-187页

作者： Iouzalen, L Stepien, O Marche, P Univ Paris 05 Fac Med Necker Necker Med Sch Dept PharmacolCNRSURA 1482 F-75015 Paris France

Angiotensin II (AII), an important hypertrophic factor in the cardiovascular system, exerts most of its known effects in vivo through the AII receptor type 1 (AT(1)) subclass of AII receptors. These receptors are also responsible for the growth-related effects of AII in cultured vascular smooth muscle cells (VSMCs). We presently investigated the effects of BAY 10-6734 (Embusartan), a new orally active AT(1) antagonist, on VSMC growth and proliferation of cultured VSMCs isolated from the aortae of Wistar Kyoto rats and spontaneously hypertensive rats. BAY 10-6734 and losartan (considered as AT(1) receptor antagonist of reference), as well as their respective active metabolites, were studied for their inhibition of: 1) [I-125]AII binding to its receptors, 2) AII-induced DNA and protein synthesis (by measuring the incorporation of 5-bromo-2'-deoxyuridine and [H-3]L-leucine, respectively), and 3) AII-induced variations in intracellular Ca2+ concentration, using cells labeled with Fura-2. All of the tested compounds inhibited the aforementioned parameters in a concentration-dependent manner. Half-maximal inhibitory concentration values indicated that BAY 10-6734 was significantly more potent than losartan and that spontaneously hypertensive rat-derived VSMCs were more sensitive than Wistar Kyoto rat-derived ones. Neither BAY 10-6734 nor losartan affected the intracellular Ca2+ concentration of unstimulated VSMCs but both compounds inhibited both AII-induced Ca2+ mobilization from internal stores and Ca2+ influx. Neither compound affected arginine-vasopressin-, basic fibroblast growth factor-, or serum-induced DNA and protein synthesis. BAY 10-6734 appears therefore as a potent and specific new inhibitor of AII-induced growth-related events in VSMCs.

关键词：血管紧张素ⅱ/代谢钙/代谢细胞分裂/药物作用细胞培养的胞质溶胶/药物作用胞质溶胶/代谢 DNA/生物合成二氢吡啶类/药理学咪唑类/药理学洛沙坦/药理学肌平滑血管/细胞学肌平滑血管/药物作用蛋白质生物合成放射配体测定大鼠近交SHR 大鼠近交WKY 受体血管紧张素 1型受体血管紧张素 2型受体血管紧张素/拮抗剂和抑制剂种特异性四唑类/药理学动物男(雄)性大鼠

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Synthesis and pharmacological evaluation of new pyrazolidine-3,5-diones as AT₁ angiotensin II receptor antagonists

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JOURNAL OF MEDICINAL CHEMISTRY 2000年第14期43卷 2685-2697页

作者： Le Bourdonnec, B Meulon, E Yous, S Goossens, JF Houssin, R Hénichart, JP Univ Lille 2 Fac Sci Pharmaceut & Biol Inst Chim Pharmaceut Albert Lespagnol F-59006 Lille France Univ Lille 2 Fac Sci Pharmaceut & Biol Chim Analyt Lab F-59006 Lille France

On the basis of the structure of the non-peptide receptor antagonist irbesartan, a new series of AT(1) ligands was designed. In these compounds the central imidazolone nucleus of irbesartan was replaced by a pyrazolidine-3,5-dione structure. The key intermediate N-alkylpyrazolidine3,5-dioneswere synthesized according to a new and general method. The most active compounds possess a spirocyclopentane ring at position 4, a linear butyl chain at position 1, and the [2'-(5-tetrazolyl)biphenyl-4-yl]methyl or [2'-(benzoylaminosulfonyl)biphenyl-4-yl] group at position 2. Affinity toward the AT(1) and AT(2) receptors was assessed by the ability of the compounds to competitively displace [H-3]AII from its specific binding sites. The most active compounds, 28 and 48, displayed high affinity for the AT(1) receptor, good selectivity AT(1) versus AT(2), and potent in vitro antagonist activity.

关键词：血管紧张素ⅱ/代谢血管紧张素受体拮抗剂结合竞争性联苯化合物/化学钙/代谢配体吡唑类/化学合成吡唑类/化学吡唑类/代谢吡唑类/药理学受体血管紧张素 1型受体血管紧张素 2型受体血管紧张素/代谢螺环化合物/化学合成螺环化合物/化学螺环化合物/代谢螺环化合物/药理学构效关系四唑类/化学肿瘤细胞培养的人类

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Natriuretic peptide receptor-A negatively regulates mitogen-activated protein kinase and proliferation of mesangial cells: Role of cGMP-dependent protein kinase

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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 2000年第2期271卷 374-379页

作者： Pandey, KN Nguyen, HT Li, M Boyle, JW Tulane Univ Sch Med Dept Physiol New Orleans LA 70112 USA

We have examined the effect of atrial natriuretic peptide (ANP) and its guanylyl cyclase/natriuretic peptide receptor-A (NPRA) on mitogen-activated protein kinase/extracellular signal-regulated kinase 2 (MAPK/ERK2) activity in rat mesangial cells overexpressing NPRA. Agonist hormones such as platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), angiotensin II (ANG II), and endothelin-1 (ET-1) stimulated 2.5- to 3.5-fold immunoreactive MAPK/ERK2 activity in these cells. ANP inhibited agonist-stimulated activity of MAPK/ERK2 by 65-75% in cells overexpressing NPRA, whereas in vector-transfected cells, its inhibitory effect was only 18-20%. NPRA antagonist A71915 and KT5823, a specific inhibitor of cGMP-dependent protein kinase (PKG) completely reversed the inhibitory effect of ANP on MAPK/ERK2 activity. ANP also inhibited the PDGF-stimulated [H-3]thymidine uptake by almost 70% in cells overexpressing NPRA, as compared with only 20-25% inhibition in vector-transfected cells. These results demonstrate that ANP/NPRA system negatively regulates MAPK/ERK2 activity and proliferation of mesangial cells in a PKG-dependent manner. (C) 2000 Academic Press.

关键词：血管紧张素ⅱ/代谢心钠素/代谢细胞分裂细胞培养的环GMP/代谢环GMP依赖性蛋白激酶类/生理学内皮缩血管肽1/代谢酶抑制剂/代谢成纤维细胞生长因子/代谢肾小球膜/细胞学肾小球膜/代谢鸟苷酸环化酶/拮抗剂和抑制剂鸟苷酸环化酶/代谢丝裂原活化蛋白激酶1/拮抗剂和抑制剂丝裂原活化蛋白激酶1/代谢肽碎片/代谢血小板源性生长因子/代谢沉淀素试验蛋白激酶抑制剂蛋白激酶类/代谢受体心钠素/拮抗剂和抑制剂受体心钠素/代谢四氢异喹啉类胸苷/代谢时间因素转染动物大鼠

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