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Nitric Oxide-Superoxide Interactions in Endothelial Cell Dysfunction

一氧化氮-超氧化物相互作用在内皮细胞功能障碍中的作用

基本信息

批准号：
8051607
负责人：
MAHENDRA KAVDIA
金额：
$ 34.62万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-14 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8051607
关键词：
Antioxidants Apoptosis Biological Availability Biological Process Blood Vessels Blood flow Cells Complex Computer Simulation Data Development Diabetes Mellitus Endothelial Cells Endothelium Environmental Risk Factor Enzymes Feedback Free Radical Formation Functional disorder Generations Glucose Goals Human Hyperglycemia Impairment In Vitro Kinetics Lipid Peroxidation Literature Measurement Measures Mediating Microcirculation Modeling Molecular Nitrates Nitric Oxide Nitric Oxide Synthase Nitrites Oxidative Stress Pathway interactions Peroxonitrite Process Production Reaction Reactive Nitrogen Species Reactive Oxygen Species Regulation Research Simulate Superoxide Dismutase Superoxides System Testing Time Tissues Umbilical vein Vasodilation abstracting cell injury design diabetes mellitus therapy diabetic human NOS3 protein improved multi-scale modeling prevent research study response shear stress therapy development

项目摘要

Abstract Endothelial cell (EC) dysfunction is a common pathogenic framework of many of the diabetes-related micro- and macro- vascular complications. Reduced bioavailability of EC-released nitric oxide (NO) is a primary marker generally used for EC dysfunction. However, the molecular mechanisms of hyperglycemia induced reduced NO bioavailability remain poorly understood. [We hypothesize that the diabetic endothelial cell dysfunction/reduced NO bioavailability is mediated by reactive oxygen species (ROS) and is a results of increased interaction of NO and superoxide (O2-) at the endothelial cell level. The increased interactions results in higher peroxynitrite (ONOO-) formation, shifting nitric oxide synthase (eNOS) activity from NO production to O2¿ production, and EC damage. The deleterious effects can be prevented by reducing ROS formation and concentration. Specific aims are designed to test these hypotheses. Aim1. Determine the EC release of NO and O2- and cell damage in hyperglycemic conditions. Hypotheses are: i) the high glucose causes endothelial dysfunction over long periods by increasing ONOO- and O2- formation and ii) reduction in O2- formation is key to reducing endothelial dysfunction. We will perform the following experiments: i) determining the effect of high glucose on eNOS and NA(D)PH expressions, NO and superoxide releases, endothelial cell lipid peroxidation (an indicator of peroxynitrite formation) and apoptosis in human umbilical vein endothelial cells (HUVECs) over short and long time-periods, and ii) determining whether increasing NO or decreasing O2- formation will be effective in preventing effects of high glucose. Aim2. Develop a reaction kinetic-transport computational model to simulate experiments of Aim1 and predict levels of NO, O2- and ONOO- at EC level. Hypotheses are: i) the NO concentration is reduced and ONOO- is increased due to high interaction between NO and O2- even though the NO release from endothelial cell increases in high glucose over short periods and ii) the NO concentration increases and ONOO- concentration decreases when O2- formation or concentration is reduced in high glucose. Aim3. Develop a multi-scale computational model for NO, ROS (O2-), and reactive nitrogen species (RNS; ONOO-) transport in the microcirculation underlying the process of oxidative stress. Hypotheses are: i) endothelial cell dysfunction is a results of higher superoxide formation, ii) a reduction in ROS formation enhances NO bioavailability and iii) increased superoxide dismutase levels not only reduces the O2- levels but also increases the NO levels, and reduces NO formation through feedback mechanism. At EC level, we will model the regulation of eNOS and the release of NO and O2-. At tissue level, we will model a volume of tissue containing an arteriolar blood vessel and simulate transport of NO, ROS and RNS.] This combined experimental & computational approach is critical in our understanding of molecular mechanism of EC dysfunction and examine the potential therapies to treat EC dysfunction related vascular complications. Project Narrative Endothelial cell (EC) dysfunction is a common pathogenic framework of many of the diabetes-related micro- and macro- vascular complications. The molecular mechanisms of hyperglycemia induced endothelial cell dysfunction remain poorly understood. The proposed research will use integrated computational and experimental approaches to assess endothelial cell dysfunction caused by oxidative stress due to high glucose at the molecular, cellular and tissue levels. The integrated experimental measurements and computational modeling of oxidative stress will provide an optimum set of parameters that will not only improve endothelial cell dysfunction/NO bioavailability but also will guide us in the development of therapies for diabetes related vascular complications.

摘要

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Induced peroxidase and cytoprotective enzyme expressions support adaptation of HUVECs to sustain subsequent H2O2 exposure.

诱导的过氧化物酶和细胞保护酶表达支持 HUVEC 的适应以维持随后的 H2O2 暴露。

DOI：
10.1016/j.mvr.2015.09.003
发表时间：
2016-01
期刊：
Microvascular research
影响因子：
3.1
作者：
Patel H;Chen J;Kavdia M
通讯作者：
Kavdia M

Modeling of biopterin-dependent pathways of eNOS for nitric oxide and superoxide production.

DOI：
10.1016/j.freeradbiomed.2011.06.009
发表时间：
2011-10-01
期刊：
Free radical biology & medicine
影响因子：
7.4
作者：
Kar S;Kavdia M
通讯作者：
Kavdia M

Computational insights into the role of glutathione in oxidative stress.

DOI：
10.2174/1567202611310020011
发表时间：
2013-05
期刊：
Current neurovascular research
影响因子：
2.1
作者：
Caitlin E Presnell;Gaurav Bhatti;L. Numan;M. Lerche;Salem K Alkhateeb;M. Ghalib;M. Shammaa;M. Kavdia-M.
通讯作者：
Caitlin E Presnell;Gaurav Bhatti;L. Numan;M. Lerche;Salem K Alkhateeb;M. Ghalib;M. Shammaa;M. Kavdia-M.

NO/peroxynitrite dynamics of high glucose-exposed HUVECs: chemiluminescent measurement and computational model.