Role of MMPs in AngII induced abdominal aortic aneurysms

要验证的中心假设是血管紧张素II （AngII）诱导的腹主动脉瘤（AAAs）的发生和成熟是由特定的基质金属蛋白酶（MMP）介导的，该蛋白酶通过白细胞特异性机制分泌和/或激活。为了验证这一假设，我们提出以下目标：目标1。确定是否有特定的MMP对AngII诱导的AAA负责。为了确定特定MMP的作用，我们将使用具有特定MMP基因工程缺陷的小鼠。我们将把重点放在MMP-2、-9和-12上，基于它们在动脉瘤组织中的存在以及它们在疾病过程中先前推断的作用。此外，我们将确定MMPs及其内源性抑制剂在进化和成熟动脉瘤组织中的时间序列。目标2。确定AngII是否诱导白细胞释放MMPs和/或增强邻近血管细胞分泌MMPs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MMP+/+或-/-小鼠的骨髓细胞将用于重新填充MMP+/+受体小鼠。目标3。确定AngII对白细胞依赖性调节MMP活性的作用机制。我们将确定AngII是否对培养细胞中特异性MMPs的合成和分泌产生直接影响。此外，我们将确定AngII是否导致MMPs激活增加。目标4。确定在形成AAAs后给予选择性抑制剂时MMP抑制的效果。在初步研究中，我们证明了MMPs的抑制作用阻止了血管血管诱导的AAA的发生。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要么减少已经形成的AAA的进展，要么逆转其病理。可以想象，MMPs在已经形成的AAA的重塑过程中发挥着不同的作用，而不是它们在疾病发生中的作用。因此，初步研究将确定广泛特异性的MMP抑制剂对已形成的AAA成熟过程的影响。后续研究将根据Specific Aims 1-3中获得的数据，使用更具选择性的MMP抑制剂。本研究的意义在于阐明了AA形成和成熟的机制，并强调了该疾病的药物治疗的潜在发展。

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.