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）诱导的腹主动脉动脉瘤的起始和成熟（AAA是由特定的基质金属蛋白酶（MMP）介导的，这些基质金属蛋白酶（MMP）是通过白血病细胞特定的机制来测试特定的，我们的特定指标，以下是一个特定的目标：以下是一定的，我们的目标是以下确定。为了确定特定的MMP的作用，我们将使用特定MMP的遗传性缺乏症，我们将基于它们在动脉瘤组织中的疾病及其序列的序列中的序列，将其重点放在MMP -2，-9和-12上。在进化和成熟的动脉瘤组织中。用于重新填充MMP+/+受体小鼠。 AIM 3。确定ANGII对白细胞依赖性调节MMP活性的机制。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，我们将定义ANGII是否导致MMP的激活增加。 AIM 4。确定AAAS形成后选择性抑制剂时MMP抑制作用的影响。在初步研究中，我们证明了对MMP的抑制阻止了Angii诱导的AAA的启动。但是，在人类疾病中，超声用于检测已经形成的AAA，因此有效的药理学治疗必须降低进展或逆转已建立的AAA的病理。与其在疾病的启动中的作用相比，MMP在已建立的AAA的重塑过程中起着不同的作用。因此，初步研究将确定广泛特异性MMP抑制剂对已经形成的AAA成熟过程的影响。随后的研究将根据特定目标1-3中获得的数据使用更多的MMP抑制剂。这项研究的意义与AA形成和成熟的机制的描述有关，重点是该疾病药理治疗的潜在发展。