GSTs: Oxidative Stress in Early Atherosclerosis

GST：早期动脉粥样硬化中的氧化应激

• 批准号: 6473227
• 负责人: PAUL J BOOR
• 金额: $ 29.8万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6473227
• 关键词: acrolein; aldehydes; atherosclerosis; atherosclerotic plaque; coronary disorder; enzyme activity; enzyme induction /repression; enzyme mechanism; free radical oxygen; genetically modified animals; glutathione transferase; human tissue; immunocytochemistry; immunoelectron microscopy; in situ hybridization; isozymes; laboratory mouse; lipid peroxides; northern blottings; oxidative stress; pathologic process; tissue /cell culture; vascular smooth muscle; western blottings

Atherosclerosis is a major cause of morbidity and mortality. Oxidative stress has been strongly implicated in the pathogenesis of atherosclerosis, but few studies have addressed the mechanisms by which the vascular wall defends against oxidant, or electrophilic, injury. Our recent data show that a specific subtype of glutathione S-transferase (GST), GST A4-4, is selectively induced in vascular smooth muscle cells (VSMCs) of rat aorta in response to electrophilic injury caused by alpha, beta-unsaturated aldehydes such as acrolein, 4-hydroxynonenal (4-HNE) and 4-hydroxyhexenal (4-HHE), which are toxic end products of lipid peroxidation implicated in the pathogenesis of atherosclerosis. Our recent data in human tissue also supports a role for HGST A4-4 in the pathogenesis of atherosclerosis. Our recent data in human tissue also supports a role for HGST A4-4 in the atherosclerotic plaque. Our hypothesis is that the human vascular GST isozyme, HGST A4-4, functions in the cell's defense against highly reactive alpha, beta- unsaturated aldehydes that are toxic end products of lipid peroxidation, and are implicated in the pathogenesis of atherosclerosis. We expect hGST A4-4 is induced in vascular smooth muscle cells (VSMC) and endothelium during development of the early human atherosclerotic plaque in response to oxidative stress. By manipulating this enzyme in cultured vascular cells from rat, and in genetically altered in vivo mouse models (GST-/-; apoE-/-; a double knock of apoE and GST) we will be able to alter the course of oxidative injury and atherogenesis. Using human blood vessels , our Specific Aim #1 will determine if HGST 4-4 induction and accumulation of suspected aldehyde/aldehyde adducts are early markers of oxidative injury in the early or "fibrous" human atherosclerotic plaque. In Specific Aim #2, we will utilize already- developed rat VSMC, and endothelial cells made resistant to alpha, beta- unsaturated aldehydes, to examine the role of GST during oxidative/atherosclerotic stress. In Specific Aim #3 we will use a recently developed genetically altered mouse GST during oxidative/atherosclerotic stress. In Specific Aim #3 we will use a recently developed genetically altered mouse GST knockout of GST and apoE, to manipulate GST A4-4 in order to worsen/hasten the development of atherosclerosis. These studies will focus on early events during oxidative damage and defense mechanisms in the vascular wall, so that therapeutic strategies to prevent initiation and propagation of the atherosclerotic plaque may be devised.

动脉粥样硬化是发病率和死亡率的主要原因。氧化应激与动脉粥样硬化的发病机制密切相关，但很少有研究涉及血管壁防御氧化剂或亲电损伤的机制。我们最近的数据表明，在大鼠主动脉血管平滑肌细胞（VSMC）中，选择性地诱导谷胱甘肽S-转移酶（GST）的一个特定亚型GSTA 4 -4响应于α，β-不饱和醛如丙烯醛、4-羟基壬烯醛（4-HNE）和4-羟基己烯醛（4-HHE）引起的亲电损伤，其是与动脉粥样硬化发病机制有关的脂质过氧化的有毒终产物。我们最近在人体组织中的数据也支持HGST A4-4在动脉粥样硬化发病机制中的作用。我们最近在人体组织中的数据也支持HGST A4-4在动脉粥样硬化斑块中的作用。我们的假设是人血管GST同工酶HGST A4-4在细胞防御高反应性α，β-不饱和醛中起作用，所述醛是脂质过氧化的毒性终产物，并且与动脉粥样硬化的发病机制有关。我们预期hGST A4-4在血管平滑肌细胞（VSMC）和内皮细胞中诱导，在早期人类动脉粥样硬化斑块的发展过程中响应于氧化应激。通过在来自大鼠的培养血管细胞中以及在遗传改变的体内小鼠模型（GST-/-; apoE-/-; apoE和GST的双重敲除）中操纵这种酶，我们将能够改变氧化损伤和动脉粥样硬化形成的过程。使用人血管，我们的特定目标#1将确定HGST 4-4诱导和疑似醛/醛加合物的积累是否是早期或“纤维性”人动脉粥样硬化斑块中氧化损伤的早期标志物。在具体目标#2中，我们将利用已经开发的大鼠VSMC和对α，β-不饱和醛具有抗性的内皮细胞来检查GST在氧化/动脉粥样硬化应激期间的作用。在具体目标#3中，我们将在氧化/动脉粥样硬化应激期间使用最近开发的基因改变的小鼠GST。在具体目标#3中，我们将使用最近开发的GST和apoE的基因改变的小鼠GST敲除来操纵GST A4-4以恶化/加速动脉粥样硬化的发展。这些研究将集中在氧化损伤和防御机制在血管壁的早期事件，使治疗策略，以防止动脉粥样硬化斑块的启动和传播可能会被设计出来。