Regulation of NADPH Oxidase by Angiotensin II-Role in Myometrial Hypertrophy

血管紧张素 II 调节 NADPH 氧化酶在子宫肌肥大中的作用

基本信息

批准号：
7208975
负责人：
XIAOLAN CUI
金额：
$ 7.45万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-03-20 至 2010-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7208975
关键词：
Angiotensin II Angiotensin II Receptor Angiotensins Apoptosis Biochemical Blood Vessels Calcium Cardiac Myocytes Catalytic Domain Caveolae Caveolins Cell Line Cell membrane Cells Cellular biology Data Discipline of obstetrics Elements Epidermal Growth Factor Receptor Failure Fetal Growth Fibrosis GTP-Binding Proteins Gene Family Generations Gonadal Steroid Hormones Growth Growth Factor Hand Human Hyperplasia Hypertrophy Immunohistochemistry Infection Ischemia Leiomyoma Link Localized Mechanics Mediating Membrane Metabolism Methods Minor Molecular Biology Molecular Chaperones Muscle Contraction Muscle Proteins Myocardium Myometrial NADPH Oxidase Pathology Pathway interactions Physiological Physiological Processes Physiological reperfusion Plasma Play Pregnancy Pregnant Women Premature Birth Process Production Protein Biosynthesis Protein Isoforms Proteins Reactive Oxygen Species Receptor, Angiotensin, Type 1 Regulation Renin-Angiotensin System Reperfusion Therapy Research Reverse Transcriptase Polymerase Chain Reaction Role Signal Pathway Signal Transduction Signal Transduction Pathway Site Smooth Muscle Smooth Muscle Myocytes Somatotropin Specificity Stress Stretching Tissues Transcriptional Activation Uncertainty Up-Regulation Uterus Vascular Smooth Muscle Vascular remodeling Vasopressins angiogenesis carcinogenesis caveolin 1 cell type cytokine inhibitor/antagonist interest myometrium protein expression receptor release of sequestered calcium ion into cytoplasm uterine smooth muscle cell

Angiotensin II Angiotensin II Receptor Angiotensins Apoptosis Biochemical Blood Vessels Calcium Cardiac Myocytes Catalytic Domain Caveolae Caveolins Cell Line Cell membrane Cells Cellular biology Data Discipline of obstetrics Elements Epidermal Growth Factor Receptor Failure Fetal Growth Fibrosis GTP-Binding Proteins Gene Family Generations Gonadal Steroid Hormones Growth Growth Factor Hand Human Hyperplasia Hypertrophy Immunohistochemistry Infection Ischemia Leiomyoma Link Localized Mechanics Mediating Membrane Metabolism Methods Minor Molecular Biology Molecular Chaperones Muscle Contraction Muscle Proteins Myocardium Myometrial NADPH Oxidase Pathology Pathway interactions Physiological Physiological Processes Physiological reperfusion Plasma Play Pregnancy Pregnant Women Premature Birth Process Production Protein Biosynthesis Protein Isoforms Proteins Reactive Oxygen Species Receptor, Angiotensin, Type 1 Regulation Renin-Angiotensin System Reperfusion Therapy Research Reverse Transcriptase Polymerase Chain Reaction Role Signal Pathway Signal Transduction Signal Transduction Pathway Site Smooth Muscle Smooth Muscle Myocytes Somatotropin Specificity Stress Stretching Tissues Transcriptional Activation Uncertainty Up-Regulation Uterus Vascular Smooth Muscle Vascular remodeling Vasopressins angiogenesis carcinogenesis caveolin 1 cell type cytokine inhibitor/antagonist interest myometrium protein expression receptor release of sequestered calcium ion into cytoplasm uterine smooth muscle cell

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项目摘要

DESCRIPTION (provided by applicant): Uterine hypertrophy is a physiological process occurring in pregnancy to accommodate fetal growth and the need for contraction at delivery. Growth factors, sex hormones and cytokines are known to stimulate uterine smooth muscle growth during normal pregnancy or fibrosis. Angiotensin II is a well documented vascular smooth muscle growth factor. However, the role of angiotensin II in uterine growth is not well defined, despite the fact that its concentration is increased and there is a significant switch in myometrial receptor subtype towards the type 1 angiotensin II receptor in pregnant women. NADPH oxidase isoforms, via generation of reactive oxygen species, have been shown to be responsible for the growth promoting effect of angiotensin II which is mediated by type 1 receptor in vascular smooth muscle and cardiac myocytes. We have identified several NADPH oxidase isoforms in human myometrium and in a human uterine smooth muscle cell line. We also found that a NADPH oxidase inhibitor blocked angiotensin ll-induced production of reactive oxygen species as well as uterine smooth muscle protein synthesis. Therefore, we hypothesize that angiotensin II plays an important role in myometrial growth during pregnancy via activation of NADPH oxidase, which is dependent on the type 1 angiotensin II receptor and downstream signaling pathways. We further hypothesize that NADPH oxidase is localized and activated in caveolae, the plasma membrane structures where several elements of a proposed signal transduction pathway were found. These include angiotensin II type 1 receptor, the catalytic unit of NADPH oxidase isoform 1 (Nox1), G proteins, and epidermal growth factor receptor. We will employ a combination of molecular biology, cell biology, and biochemical methods to study, in the uterine smooth muscle cell line, the following specific aims: 1) The role of angiotensin II in regulation of NADPH oxidase expression and activation in myometrial smooth muscle cells; and 2) The role of NADPH oxidase in angiotensin II receptor-mediated myometrial growth (hypertrophy) and signaling. Currently there is a great deal of interest in the role of reactive oxygen species in obstetric pathologies. It is known that many cases of preterm delivery are associated with infection where cytokines induce reactive oxygen species production. Excessive generation of reactive oxygen species contributes to contractile failure, rigor and calcium overload. Thus we predict that the angiotensin II-NADPH oxidase-reactive oxygen species pathway plays a role in labor process as well.

描述（由申请人提供）：子宫肥大是一种生理过程，以适应胎儿生长和分娩时收缩的需求。已知生长因子，性激素和细胞因子在正常妊娠或纤维化期间刺激子宫平滑肌生长。血管紧张素II是文化良好的血管平滑肌生长因子。然而，尽管其浓度升高并且肌层受体亚型向孕妇的1型血管紧张素II受体有显着的转换，但血管紧张素II在子宫生长中的作用尚未得到很好的定义。 NADPH氧化酶同工型通过活性氧的产生，已被证明是血管紧张素II的生长促进作用的原因，血管紧张素II由血管平滑肌和心肌细胞中的1型受体介导。我们已经确定了人肌层和人子宫平滑肌细胞系中的几种NADPH氧化酶同工型。我们还发现，NADPH氧化酶抑制剂阻断了血管紧张素LL诱导的活性氧以及子宫平滑肌蛋白的合成。因此，我们假设血管紧张素II通过激活NADPH氧化酶在怀孕期间的肌层生长中起重要作用，而NADPH氧化酶取决于1型血管紧张素II受体和下游信号传导途径。我们进一步假设NADPH氧化酶是局部局部并激活的，该小窝是质膜结构，其中发现了所提出的信号转导途径的几个元素。这些包括血管紧张素II型1受体，NADPH氧化酶同工型1（NOX1），G蛋白和表皮生长因子受体的催化单元。我们将采用分子生物学，细胞生物学和生化方法的结合，在子宫平滑肌细胞系中研究以下特定目的：1）血管紧张素II在调节NADPH氧化酶表达和在子宫肌层平滑肌细胞中激活的作用； 2）NADPH氧化酶在血管紧张素II受体介导的肌层生长（肥大）和信号传导中的作用。目前，对活性氧在产科病理中的作用引起了极大的兴趣。众所周知，许多早产的病例与细胞因子诱导活性氧产生的感染有关。活性氧的产生过多会导致收缩衰竭，严格和钙超负荷。因此，我们预测血管紧张素II-NADPH氧化酶反应性氧途径也在劳动过程中起作用。