GSTs: Oxidative Stress in Early Atherosclerosis

GST：早期动脉粥样硬化中的氧化应激

基本信息

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
项目类别：
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

项目摘要

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理非常重要，但是很少有研究解决了血管壁抗氧化剂或亲电损伤的机制。 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-羟基己纳尔（4-HHE），这是与动脉粥样硬化的发病机理有关的脂质过氧化的有毒最终产物。我们在人体组织中的最新数据还支持HGST A4-4在动脉粥样硬化的发病机理中的作用。我们在人体组织中的最新数据还支持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在细胞防御高度反应性α的防御中起作用，β-未饱和醛是脂质过氧化的有毒终产物，并且与动脉粥样硬化的病原体有关。我们预计，在早期人动脉粥样硬化斑块的发育过程中，血管平滑肌细胞（VSMC）和内皮会诱导HGST A4-4。通过在大鼠的培养血管细胞中操纵这种酶，并在遗传变化的体内小鼠模型（GST - / - ; APOE-/ - ； APOE和GST的双重敲击）中，我们将能够改变氧化损伤和动脉粥样硬化的过程。使用人体血管，我们的具体目标＃1将确定HGST 4-4诱导和可疑醛/醛加合物的积累是早期或“纤维状”人类动脉粥样硬化斑块中氧化损伤的早期标志。在特定的目标＃2中，我们将利用已经开发的大鼠VSMC，内皮细胞对抗α-不饱和醛的抗性，以检查GST在氧化/动脉粥样硬化胁迫中的作用。在特定的目标＃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遗传改变的小鼠GST。在特定的目标＃3中，我们将使用最近开发的遗传改变的小鼠GST敲除GST和APOE，以操纵GST A4-4，以使动脉粥样硬化的发展恶化/加速。这些研究将集中在血管壁中氧化损伤和防御机制期间的早期事件上，以便可以设计出预防动脉粥样硬化斑块开始和传播的治疗策略。