Role of MMPs in AngII induced abdominal aortic aneurysms

MMPs 在 AngII 诱导的腹主动脉瘤中的作用

• 批准号: 6756731
• 负责人: Alan Daugherty
• 金额: $ 8.49万
• 依托单位: UNIVERSITY OF KENTUCKY
• 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 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6756731
• 关键词: ACE inhibitors; SDS polyacrylamide gel electrophoresis; angiotensin II; angiotensin receptor; aorta aneurysm; apolipoproteins; biological signal transduction; bone marrow transplantation; cell population study; disease /disorder etiology; enzyme activity; enzyme biosynthesis; enzyme induction /repression; enzyme mechanism; genetically modified animals; hyperlipidemia; immunocytochemistry; laboratory mouse; low density lipoprotein receptor; metalloendopeptidases; tissue /cell culture; tissue /cell preparation; tissue inhibitor of metalloproteinases; vascular endothelium; western blottings

The central hypothesis to be tested is that the initiation and maturation of angiotensin II (AngII)-induced abdominal aortic aneurysms (AAAs is mediated by a specific matrix metalloproteinase (MMP) that is secreted and/or activated via a leukocyte-specific mechanism. To test this hypothesis, we propose the following aims: Aim 1. Determine whether a specific MMP is responsible for AngII- induced AAA.. To identify the action of a specific MMP, we will use mice with genetically engineered deficiencies of specific MMPs. We will focus our efforts on MMP-2, -9, and -12, based on the demonstration of their presence in aneurysmal tissue and their previous inferred roles in the disease process. Further, we will define the temporal sequence of elaboration of MMPs and their endogenous inhibitors in evolving and mature aneurysmal tissue. Aim 2. Determine whether AngII induces the release of MMPs from leukocytes and/or enhances the activation of MMPs secreted by neighboring vascular cells. To determine the direct contribution of AngII on MMP mediated AAA formation, we will perform bone marrow transplantation studies in which bone marrow cells from MMP+/+ or -/- mice will be used to repopulate MMP+/+ recipient mice. Aim 3. Determine the mechanism of AngII on leukocyte-dependent regulation of MMP activity. We will determine whether AngII exerts a direct effect on the synthesis and secretion of specific MMPs in cultured cells. Further, we will define whether AngII results in increased activation of MMPs. Aim 4. Determine the effects of MMP inhibition when selective inhibitors are administrated after the formation of AAAs. In preliminary studies we demonstrated that inhibition of MMPs prevented the initiation of AngII-induced AAA. However, in the human disease ultrasound is used to detect an already formed AAA, and thus an effective pharmacologic treatment would have to either reduce the progression or reverse the pathology of an established AAA. It is conceivable that MMPs play a different role in the remodeling process in established AAAs, as compared to their role in the initiation of the disease. Therefore, initial studies will determine the effects of broad specificity MMP inhibitors on the maturation process of an already formed AAA. Subsequent studies will use more selective inhibitors of MMPs based on data obtained in Specific Aims 1-3. The significance of this research relates to delineation of mechanism for AA formation and maturation, with emphasis on potential development of pharmacological treatments of the disease.

要测试的中心假设是血管紧张素 II (AngII) 诱导的腹主动脉瘤 (AAA) 的起始和成熟是由特定的基质金属蛋白酶 (MMP) 介导的，MMP 通过白细胞特异性机制分泌和/或激活。为了检验这一假设，我们提出以下目标： 目标 1. 确定特定 MMP 是否负责 AngII 诱导的 AAA。为了确定特定 MMP 的作用，我们将使用我们将重点关注 MMP-2、-9 和 -12，基于它们在动脉瘤组织中的存在以及它们先前推断的在疾病过程中的作用。确定 MMP 及其内源性抑制剂在进化和成熟动脉瘤组织中的形成时间顺序。 目标 2. 确定 AngII 是否诱导白细胞释放 MMP。和/或增强邻近血管细胞分泌的 MMP 的激活为了确定 AngII 对 MMP 介导的 AAA 形成的直接贡献，我们将进行骨髓移植研究，其中来自 MMP+/+ 或 -/- 小鼠的骨髓细胞将被移植。用于重新填充 MMP+/+ 受体小鼠。目标 3. 确定 AngII 对白细胞依赖性 MMP 活性调节的机制。我们将确定AngII是否对培养细胞中特定MMP的合成和分泌产生直接影响。此外，我们将确定 AngII 是否会导致 MMP 激活增加。目标 4. 确定 AAA 形成后施用选择性抑制剂时 MMP 抑制的效果。在初步研究中，我们证明 MMP 的抑制可以阻止 AngII 诱导的 AAA 的启动。然而，在人类疾病中，超声用于检测已经形成的 AAA，因此有效的药物治疗必须减缓已形成的 AAA 的进展或逆转其病理学。可以想象，MMP 在已建立的 AAA 的重塑过程中发挥着不同的作用，与其在疾病发生中的作用相比。因此，初步研究将确定广泛特异性 MMP 抑制剂对已形成的 AAA 成熟过程的影响。后续研究将根据具体目标 1-3 中获得的数据使用更具选择性的 MMP 抑制剂。这项研究的意义在于阐明 AA 形成和成熟的机制，重点是该疾病药物治疗的潜在发展。