Expression of PKG in Vascular Smooth Muscle Cells

PKG在血管平滑肌细胞中的表达

基本信息

批准号：
8448328
负责人：
Thomas M. Lincoln
金额：
$ 35.34万
依托单位：
UNIVERSITY OF SOUTH ALABAMA
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-01-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8448328
关键词：
Accounting Address Animal Model Atherosclerosis Blood Vessels Blood flow Cardiovascular Diseases Carotid Arteries Cell Culture Techniques Cells Cessation of life Contractile Proteins Contracts Cultured Cells Cyclic GMP Cyclic GMP-Dependent Protein Kinases Disease Down-Regulation Enzymes Excision Extracellular Matrix Extracellular Matrix Proteins Failure Funding Gene Expression Genetic Growth Factor Immunoprecipitation In Vitro Inflammation Inflammation Mediators Inflammatory Injury Interleukin-1 Ischemia Knockout Mice Knowledge Laboratories Lead Learning Lesion Ligase Light Lysine Mediator of activation protein Messenger RNA Modeling Nitric Oxide Nitric Oxide Signaling Pathway Nitric Oxide Synthase Organ Pathway interactions Phenotype Platelet Activation Platelet aggregation Platelet-Derived Growth Factor Procedures Proliferating Protein Isoforms Protein-Serine-Threonine Kinases Proteins Research Role Signal Pathway Signal Transduction Site-Directed Mutagenesis Smooth Muscle Smooth Muscle Myocytes Soluble Guanylate Cyclase Stimulus Stroke TNF gene Testing Tissues Transfection Vascular Diseases Vascular Smooth Muscle Vascular remodeling Work Wound Healing cytokine genetic pedigree human NOS2A protein in vivo inhibitor/antagonist interest nitric oxide synthase II premature prevent protein expression public health relevance response response to injury restenosis restoration ubiquitin-protein ligase vascular smooth muscle cell proliferation

项目摘要

DESCRIPTION (provided by applicant): Atherosclerosis and other vascular diseases account for more deaths in the U.S. than any other cause. It is now well-understood that atherosclerosis is an inflammatory disorder whereby in response to injury and insult to the vasculature, growth factors and cytokines stimulate normal vascular smooth muscle cells (VSMC) to proliferate and secrete excessive extracellular matrix material. The resultant lesions cause disruptions in normal blood flow, platelet aggregation and activation, and eventually end-organ damage due to circulatory failure. Much research in the past two decades has identified signaling pathways in VSMC that lead to these proliferative and secretory changes. One pathway that normally blocks VSMC proliferation and secretory activity and promotes normal gene expression is the nitric oxide (NO)/cGMP pathway. Cyclic GMP activates a serine/threonine protein kinase, PKG-I, in vascular smooth muscle that leads to increases in normal contractile protein gene expression and suppresses proliferative and secretory activity. PKG-I thus is an important homeostatic control point whose activity is important for preventing excessive VSMC phenotypic modulation to the fibroproliferative state. Over the past few years, our laboratory has been interested in the mechanisms that control the expression of PKG-I in VSMC. Briefly, PKG-I expression is suppressed by inflammatory cytokines and growth factors that increase the fibroproliferative phenotype; restoration of PKG-I expression by transfection/adenoviral transduction restores the contractile phenotype of the VSMC. Hence, how inflammation controls PKG-I expression is critically important to understand in order to fully understand how these vascular disorders come about. During the previous funding period, we identified a pathway by which inflammatory cytokines regulate PKG-I expression. By inducing the expression of type II NO synthase (iNOS) in VSMC, cytokines/growth factors cause a persistent elevation in cGMP which directly causes down-regulation in the levels of PKG-I. This, in turn, is caused by cGMP-induced autophosphorylation of the PKG-Ia isoform and its ubiquitinylation. In this proposal, we will investigate the mechanisms by which PKG-Ia is ubiquitinylated in cultured VSMC, and determine whether this mechanism exists in vivo using wild- type and iNOS null mice to define the role of iNOS. The results of this proposed three-year study will shed new light on the mechanisms by which inflammation bring about vascular disorders.

描述（由申请人提供）：在美国，动脉粥样硬化和其他血管疾病造成的死亡人数比任何其他原因都要多。现在众所周知，动脉粥样硬化是一种炎症性疾病，为了应对血管系统的损伤和损伤，生长因子和细胞因子刺激正常血管平滑肌细胞（VSMC）增殖并分泌过多的细胞外基质物质。由此产生的病变会导致正常血流、血小板聚集和激活中断，并最终因循环衰竭而导致终末器官损伤。过去二十年的大量研究已经确定了 VSMC 中导致这些增殖和分泌变化的信号通路。通常阻断 VSMC 增殖和分泌活性并促进正常基因表达的一条途径是一氧化氮 (NO)/cGMP 途径。环 GMP 激活血管平滑肌中的丝氨酸/苏氨酸蛋白激酶 PKG-I，导致正常收缩蛋白基因表达增加并抑制增殖和分泌活性。因此，PKG-I是一个重要的稳态控制点，其活性对于防止VSMC表型过度调节纤维增殖状态非常重要。在过去的几年里，我们实验室一直对VSMC中PKG-I表达的控制机制感兴趣。简而言之，PKG-I 表达受到炎性细胞因子和生长因子的抑制，从而增加纤维增殖表型；通过转染/腺病毒转导恢复PKG-I表达可恢复VSMC的收缩表型。因此，为了充分了解这些血管疾病是如何发生的，了解炎症如何控制 PKG-I 表达至关重要。在之前的资助期间，我们确定了炎症细胞因子调节 PKG-I 表达的途径。通过诱导 VSMC 中 II 型一氧化氮合酶 (iNOS) 的表达，细胞因子/生长因子导致 cGMP 持续升高，从而直接导致 PKG-I 水平下调。反过来，这是由 cGMP 诱导的 PKG-Ia 亚型自身磷酸化及其泛素化引起的。在本提案中，我们将研究 PKG-Ia 在培养的 VSMC 中被泛素化的机制，并使用野生型和 iNOS 缺失小鼠确定这种机制在体内是否存在，以定义 iNOS 的作用。这项为期三年的研究结果将为炎症导致血管疾病的机制提供新的线索。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Stabilization of cGMP-dependent protein kinase G (PKG) expression in vascular smooth muscle cells: contribution of 3'UTR of its mRNA.

血管平滑肌细胞中 cGMP 依赖性蛋白激酶 G (PKG) 表达的稳定：其 mRNA 3UTR 的贡献。

DOI：
10.1093/jb/mvr003
发表时间：
2011
期刊：
Journal of biochemistry
影响因子：
2.7
作者：
Sellak,Hassan;Lincoln,ThomasM;Choi,Chung-Sik
通讯作者：
Choi,Chung-Sik

Possible involvement of Cyclic-GMP-dependent protein kinase on matrix metalloproteinase-2 expression in rat aortic smooth muscle cells.

DOI：
10.1007/s11010-012-1339-2
发表时间：
2012-09
期刊：
MOLECULAR AND CELLULAR BIOCHEMISTRY
影响因子：
4.3
作者：
Dey, Nupur B.;Lincoln, Thomas M.
通讯作者：
Lincoln, Thomas M.

KLF4 and SOX9 transcription factors antagonize β-catenin and inhibit TCF-activity in cancer cells.

DOI：
10.1016/j.bbamcr.2012.06.027
发表时间：
2012-10
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
影响因子：
5.1
作者：
Sellak, Hassan;Wu, Songwei;Lincoln, Thomas M.
通讯作者：
Lincoln, Thomas M.

MicroRNA-145 restores contractile vascular smooth muscle phenotype and coronary collateral growth in the metabolic syndrome.

DOI：
10.1161/atvbaha.112.301116
发表时间：
2013-04
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
0
作者：
Hutcheson R;Terry R;Chaplin J;Smith E;Musiyenko A;Russell JC;Lincoln T;Rocic P
通讯作者：
Rocic P