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NO-induced vascular smooth muscle cell motility

NO诱导血管平滑肌细胞运动

基本信息

批准号：
7541739
负责人：
AVIV HASSID
金额：
$ 35.44万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-08-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7541739
关键词：
1-Phosphatidylinositol 3-Kinase AGTR2 gene Abbreviations Accounting Alleles Analysis of Variance Angiotensin II Angiotensin Receptor Antigens Arginine Atherosclerosis Attenuated Blood Vessels Bromodeoxyuridine C-Type Natriuretic Peptide Cell membrane Chronic Cultured Cells Cyclic GMP Cyclic GMP-Dependent Protein Kinases DNA biosynthesis Event Extracellular Signal Regulated Kinases Glycine Hemagglutinin Hyperinsulinism Injury Insulin Insulin Resistance Internal Ribosome Entry Site Investigation Letters Mediating Metabolic syndrome Mitogen-Activated Protein Kinases Modeling Mus N-acetylpenicillamine Nitric Oxide Non-Insulin-Dependent Diabetes Mellitus Obesity PH Domain PTPN11 gene Pathogenesis Pathology Phenylmethylsulfonyl Fluoride Phosphatidylinositols Platelet-Derived Growth Factor Play Polymerase Chain Reaction Prevalence Protein Tyrosine Phosphatase Proteins Publications Quinoxalines Rattus Recruitment Activity Reporting Research Personnel Role S-nitro-N-acetylpenicillamine Saralasin Smooth Muscle Myocytes Sodium Dodecyl Sulfate-PAGE Testing Tyrosine Vascular Diseases adapter protein cell motility enhanced green fluorescent protein human NOS2A protein human NOS3 protein inhibitor/antagonist insight kinase inhibitor neointima formation programs protein aminoacid sequence receptor research study response vascular smooth muscle cell proliferation

项目摘要

Nitric oxide (NO)is generally considered to play a protective role in blood vessels. However, others and we have obtained evidence that this may not always be the case but the mechanisms underlying diverse responses to NO are not known. The purpose of this proposal is to test an exciting new hypothesis on the capacity of chronically elevated insulin levels to switch the role of nitric oxide from protective to deleterious substance in blood vessels. We have found that the inhibitory effects of NO on both motility and proliferation are abrogated in vascular smooth muscle cells chronically treated with insulin. These findings support a new hypothesis on the role of insulin as a switcher of vascular smooth muscle cell phenotypic responses to NO. Our preliminary results indicate that the motility-stimulatory effect of NO, uncovered by chronic insulin treatment of cultured rat aortic smooth muscle cells, is associated with increased PI 3 kinase activity and requires the functional availability of angiotensin II, of the adapter protein Gab1and the protein tyrosine phosphatase SHP2. Studies by others have found that Gab1 can be recruited to the plasma membrane via increased PIPS levels. However, the mechanistic linkage of chronic insulin treatment to Gab1 and SHP2 function has not been defined. Moreover, experiments to determine whether similar mechanisms may be applicable to abrogation of the antiproliferative effect of NO by chronic insulin treatment have not been performed. Finally, the pathophysiological significance of our results is unknown. We propose to implement the following specific aims: Aim 1. To determine whether increased angiotensin II function is necessary and/or sufficient to account for the effect of insulin on PI3K activity and NO-induced cell motility. Aim 2. To determine whether chronic insulin treatment recruits Gab1 to the cell membrane and whether insulin- independent recruitment of Gab1 or SHP2 to the cell membrane can mimic the motility-stimulatory effect of NO uncovered by chronic insulin treatment. Aim 3: To uncover mechanisms that describe how hyperinsulinemia attenuates the effect of NO as inhibitor of PDGF-induced DNA synthesis, in cultured rat aortic smooth muscle cells. Aim 4. To determine whether expression of inducible nitric oxide synthase in vascular injury enhances neointima formation in hyperinsulinemic mice, but has the opposite effect in normoinsulinemic mice or in hyperinsulinemic mice treated with an AT1 receptor antagonist.

一氧化氮(NO)通常被认为在血管中起保护作用。然而，其他人和我们已经获得了证据表明情况可能并不总是这样，但背后的机制不同对NO的反应尚不清楚。这项提议的目的是检验一个令人兴奋的新假说慢性升高的胰岛素水平将一氧化氮的作用从保护作用转换为有害作用的能力血管中的物质。我们已经发现，NO对运动和增殖的抑制作用在长期用胰岛素治疗的血管平滑肌细胞中被取消。这些发现支持一种新的胰岛素作为血管平滑肌细胞对NO表型反应的开关作用的假说。我们的初步结果表明，慢性胰岛素发现NO的运动刺激作用对培养的大鼠主动脉平滑肌细胞的处理与PI-3K活性增加和需要血管紧张素II、适配蛋白Gab1和酪氨酸蛋白的功能性可用性磷酸酶SHP2。其他人的研究发现，GAB1可以通过提高了点数水平。然而，慢性胰岛素治疗与GAB1和SHP2的机制联系尚未定义函数。此外，确定类似机制的实验是否可能适用于通过慢性胰岛素治疗消除NO的抗增殖作用已执行。最后，我们的结果的病理生理学意义尚不清楚。我们建议实施具体目标如下：目标1.确定是否有必要增加血管紧张素II的功能和/或足以解释胰岛素对PI3K活性和NO诱导的细胞运动的影响。目标2.目标确定慢性胰岛素治疗是否将GAB1招募到细胞膜，以及胰岛素是否- GAB1或SHP2在细胞膜上的独立募集可以模拟无慢性胰岛素治疗暴露。目标3：揭示描述如何高胰岛素血症减弱NO抑制PDGF诱导的大鼠DNA合成的作用主动脉平滑肌细胞。目的4.检测诱导型一氧化氮合酶(INOS)在卵巢癌中的表达血管损伤促进高胰岛素血症小鼠的新生内膜形成，但对正常胰岛素血症小鼠或用AT1受体拮抗剂治疗的高胰岛素血症小鼠。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Suppression of PKG by PDGF or nitric oxide in differentiated aortic smooth muscle cells: obligatory role of protein tyrosine phosphatase 1B.

PDGF 或一氧化氮在分化的主动脉平滑肌细胞中抑制 PKG：蛋白酪氨酸磷酸酶 1B 的必然作用。

DOI：
10.1152/ajpheart.00225.2010
发表时间：
2011
期刊：
American journal of physiology. Heart and circulatory physiology
影响因子：
0
作者：
Zhuang,Daming;Balani,Poonam;Pu,Qinghua;Thakran,Shalini;Hassid,Aviv
通讯作者：
Hassid,Aviv

Essential role of protein kinase G and decreased cytoplasmic Ca2+ levels in NO-induced inhibition of rat aortic smooth muscle cell motility.

蛋白激酶 G 和细胞质 Ca2 水平降低在 NO 诱导的大鼠主动脉平滑肌细胞运动抑制中的重要作用。

DOI：
10.1152/ajpheart.01031.2004
发表时间：
2005
期刊：
American journal of physiology. Heart and circulatory physiology
影响因子：
0
作者：
Zhuang,Daming;Ceacareanu,Alice-Corina;Ceacareanu,Bogdan;Hassid,Aviv
通讯作者：
Hassid,Aviv

Chronic insulin treatment amplifies PDGF-induced motility in differentiated aortic smooth muscle cells by suppressing the expression and function of PTP1B.

长期胰岛素治疗通过抑制 PTP1B 的表达和功能，放大 PDGF 诱导的分化主动脉平滑肌细胞的运动。

DOI：
10.1152/ajpheart.01105.2007
发表时间：
2008
期刊：
American journal of physiology. Heart and circulatory physiology
影响因子：
0
作者：
Zhuang,Daming;Pu,Qinghua;Ceacareanu,Bogdan;Chang,Yingzi;Dixit,Madhulika;Hassid,Aviv
通讯作者：
Hassid,Aviv