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：
6624246
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和死亡的主要原因。氧化应激与动脉粥样硬化的发病机制密切相关，但很少有研究探讨血管壁抵御氧化剂或亲电损伤的机制。我们最近的数据表明，谷胱甘肽 S-转移酶 (GST) 的一种特定亚型，GST A4-4，在大鼠主动脉的血管平滑肌细胞 (VSMC) 中选择性诱导，以响应 α、β-不饱和醛类引起的亲电损伤，例如如丙烯醛、4-羟基壬烯醛 (4-HNE) 和 4-羟基己烯醛 (4-HHE)，它们是涉及脂质过氧化的有毒最终产物在动脉粥样硬化的发病机制中。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，人类血管 GST 同工酶 HGST A4-4 在细胞防御高反应性 α、β-不饱和醛方面发挥作用，这些醛是脂质过氧化的有毒终产物，与动脉粥样硬化的发病机制有关。我们预计，在人类早期动脉粥样硬化斑块形成过程中，血管平滑肌细胞 (VSMC) 和内皮细胞响应氧化应激，会诱导 hGST A4-4。通过在大鼠培养的血管细胞和基因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的过程，并动脉粥样硬化。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/醛加合物的积累是否是早期或“纤维”人体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，我们将利用已发育的大鼠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转基因小鼠 GST。在具体目标#3中，我们将使用最近开发的转基因小鼠GST敲除GST和apoE来操纵GST A4-4，以恶化/加速动脉粥样硬化的发展。这些研究将重点关注血管壁氧化损伤和防御机制期间的早期事件，以便可以设计出防止动脉粥样硬化斑块发生和扩散的治疗策略。