Genistein and cAMP signaling in vascular endothelium

血管内皮细胞中的金雀异黄素和 cAMP 信号传导

基本信息

批准号：
7491164
负责人：
DONGMIN LIU
金额：
$ 23.47万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7491164
关键词：
Address Adenylate Cyclase Adhesions Aging American Animals Arteriosclerosis Biochemical Biological Biological Assay Blood Pressure Blood Vessels Cardiovascular Diseases Cardiovascular system Cell Proliferation Cell membrane Cells Chronic Condition Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cytoskeletal Modeling Data Depressed mood Development Disease Dose Elevation Endothelial Cells Estrogen Receptors Event Extravasation Foundations Functional disorder GTP-Binding Proteins Gases Gene Expression Genetic Transcription Genistein Genomics Goals Health Health Benefit Hypertension Hypotension Ingestion Intervention Isoflavones Leukocytes Mediating Mediation Messenger RNA Methods Microscope Molecular Morbidity - disease rate Nitric Oxide Nitric Oxide Synthase Nutraceutical Pathway interactions Permeability Physiological Play Polymerase Chain Reaction Population Preventive Process Production Protein Biosynthesis Protein Tyrosine Kinase Proteins Public Health RNA Range Rattus Research Ribonucleases Role Signal Pathway Signal Transduction Signaling Molecule Smooth Muscle Myocytes Soy Proteins System Testing Therapeutic Thrombin Time Vascular Diseases Vascular Endothelial Cell Vascular Endothelium analog base cellular targeting dietary supplements human NOS3 protein immunocytochemistry monolayer non-genomic novel promoter protective effect protein expression soy soy protein isolate vasoactive agent

项目摘要

DESCRIPTION (provided by applicant): The long-range goal of this research is to develop novel vasoactive agents that may be of benefit in lowering the high level of cardiovascular morbidity in the aging American population. Recent studies have shown that ingestion of soy protein associated with isoflavones may have a protective role in vasculature. Genistein, the major soy isoflavone, has various biologgical actions. However, it is not clear whether the beneficial effect of soy protein is due to genistein or other components. In addition, the cellular or molecular mechanisms underlying the vessel protective effect of soy products remain unclear. We recently found that genistein directly acts on vascular dothelial cells (EC), leading to cAMP accumulation, nitric oxide synthase (eNOS) activation and expression. Further, We demonstrated that genistein induced a rapid decrease in systemic blood pressure (BP) in rats. The objective of this application, is therefore to determine how genistein triggers the cAMP signaling pathway and thereby influencing the cAMP-related vascular function. The four following questions will be addressed: 1). How does genistein elevate cAMP, activate eNOS, and consequently stimulate nitric oxide in EC? 2) Does genistein decrease BP in animals through activation of the cAMP signaling? 3). Does elevated cAMP by genistein also alter eNOS gene expression ? 4). Does genistein protect endothelial barrier function via the cAMP signaling? We will employ cellular, molecular and biochemical analysis to determine whether genistein elevates cAMP via activation of Gs-mediated adenylate cyclase in EC. Genistein-regulated eNOS gene expression will be evaluated by ribonuclease protection assay and Real-Time PCR. The effect of genistein on endothelial barrier function, as determined by cytoskeletal reorganization and barrier permeability, will be assessed using immunocytochemistry, confocal microscope and macromolecular leakage methods. Pharmacological and molecular intervention approaches will be used to detemine the involvement of a specific pathway in mediation of genistein action. The results from these studies will establish the mechanisms of the genistein action in vasculature and thereby provide foundation for further studies to determine the effects of genistein on vascular health and diseases such as hypertension. The demonstration of the health benefits of soy isoflavones in vasculature is expected to have significant effect on public health since isoflavones are widely used as a dietary supplements.

描述（由申请人提供）：这项研究的远距离目标是开发新型的血管活性剂，在降低美国老龄化的美国人群中高水平的心血管发病率中可能有益。最近的研究表明，摄入与异黄酮有关的大豆蛋白可能在脉管系统中具有保护作用。 Genastein是主要大豆异黄酮，具有各种生物学作用。但是，尚不清楚大豆蛋白的有益作用是否是由于染料木黄酮或其他成分引起的。另外，大豆产品的血管保护作用的基础的细胞或分子机制尚不清楚。我们最近发现，染料木黄酮直接作用于血管多层细胞（EC），导致cAMP积累，一氧化氮合酶（ENOS）激活和表达。此外，我们证明了染料木黄酮会导致大鼠全身血压（BP）迅速降低。因此，该应用的目的是确定染料木黄酮如何触发cAMP信号通路，从而影响与营地相关的血管功能。将解决以下四个问题：1）。染料木黄酮如何提升cAMP，激活eNOS并因此刺激EC中的一氧化氮？ 2）通过激活cAMP信号传导，染料木黄酮会减少动物的BP吗？ 3）。染料木黄酮提高cAMP是否也会改变eNOS基因表达？ 4）。染料木黄酮是否通过cAMP信号传导保护内皮屏障功能？我们将利用细胞，分子和生化分析来确定染料木黄酮是否通过在EC中激活GS介导的腺苷酸环化酶来提升cAMP。通过核糖核酸酶保护测定和实时PCR，将评估染料木黄素调节的eNOS基因表达。通过免疫细胞化学，共聚焦显微镜和大分子分子泄漏方法，将评估染料木黄酮对内皮屏障功能的影响，由细胞骨架重组和屏障渗透率确定。药理学和分子干预方法将用于逐渐涉及特定途径参与染料木黄酮作用的介导。这些研究的结果将确定脉管系统中染料木黄酮作用的机制，从而为进一步的研究提供了基础，以确定染料木黄酮对血管健康和疾病（例如高血压）的影响。由于异黄酮被广泛用作饮食补充剂，预计大豆异黄酮在脉管系统中的健康益处的证明将对公共卫生产生重大影响。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Isoflavone genistein protects human vascular endothelial cells against tumor necrosis factor-alpha-induced apoptosis through the p38beta mitogen-activated protein kinase.

DOI：
10.1007/s10495-008-0283-9
发表时间：
2009-01
期刊：
APOPTOSIS
影响因子：
7.2
作者：
Si, Hongwei;Liu, Dongmin
通讯作者：
Liu, Dongmin

Green tea catechins and cardiovascular health: an update.

DOI：
10.2174/092986708785132979
发表时间：
2008-07
期刊：
Current medicinal chemistry
影响因子：
4.1
作者：
P. V. A. Babu;Dongmin Liu
通讯作者：
P. V. A. Babu;Dongmin Liu

Genistein ameliorates hyperglycemia in a mouse model of nongenetic type 2 diabetes.

DOI：
10.1139/h2012-005
发表时间：
2012-06
期刊：
Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme
影响因子：
0
作者：
Fu Z;Gilbert ER;Pfeiffer L;Zhang Y;Fu Y;Liu D
通讯作者：
Liu D

The flavonoid luteolin induces nitric oxide production and arterial relaxation.