Specific Secretory Phospholipase A2 Isozymes Promote Aneurysm Formation

分泌型磷脂酶A2酶（sPLA 2），特别是HA组、V组和X组 亚型，已经涉及多种炎性疾病。我们提供的证据表明， 在小鼠模型中，sPLA 2在促进腹主动脉瘤（AAA）形成中起作用。 血管疾病一种广泛特异性的sPLA 2抑制剂可显著降低 血管紧张素II（AngII）诱导的AAAs在apoE-/-小鼠中的表达。另外，表达人源化基因的转基因小鼠， 与非转基因小鼠相比，IIA组sPLA 2对AngII诱导的AAA具有增加的易感性。 这一提议的中心假设是，通过免疫组织化学方法表达的IIA组、V组和/或X组sPLA 2是由免疫组织化学方法表达的。 巨噬细胞浸润血管壁，通过促进局部释放 炎性前列腺素类这一假设基于已发表的数据和我们自己的初步发现： a）巨噬细胞浸润到腹主动脉中层是AAA的早期事件; B）V组 和X组sPLA 2蛋白存在于apoE-/-小鼠的AAA中，c）V组和X组sPLA 2蛋白的主动脉表达 在输注AngII的apoE-/-小鼠中，X组sPLA 2 mRNA增加; d）这些同工酶通过 巨噬细胞; e）这些同工酶与环氧化酶2（考克斯-2）依赖性前列腺素有关 f）用考克斯-2-选择性抑制剂处理的小鼠在应答中具有显著减少的AAA 慢性AngII输注。为了验证这一假设，我们提出鉴定特定的sPLA 2介导AAA 进展，并确定这些sPLA 2同工酶的白细胞表达的相对贡献， 致病作用（特定目标1）;定义全身与白细胞表达的 IIA组sPLA 2介导AngII诱导的AAA（特异性目的2）;并确定是否致病性 sPLA 2的作用依赖于考克斯-2活性（具体目标3）。这些研究有可能确定 AAA干预的新目标。

Secretory phospholipase A2 enzymes (sPLA2's), in particular the Group HA, Group V, and Group X subtypes, have been implicated in a wide variety of inflammatory diseases. We provide evidence that sPLA2s play a role in promoting abdominal aortic aneurysm (AAA) formation in a mouse model of this vascular disease. An sPLA2 inhibitor of broad specificity profoundly reduces both the incidence and severity of Angiotensin II (Angll)-induced AAAs in apoE-/- mice. Additionallly, transgenic mice expressing human Group IIA sPLA2 have increased susceptibility to Angll-induced AAAs compared to non-transgenic mice. The central hypothesis of this proposal is that Group IIA, Group V, and/or Group X sPLA2 expressed by macrophages infiltrating into the vessel wall accelerate AAA formation by promoting the localized release of inflammatory prostanoids. This hypothesis is based on published data and our own preliminary findings that: a) macrophage infiltration into the medial layer of the abdominal aorta is an early event in AAAs; b) Group V and Group X sPLA2 protein are present in AAAs in apoE-/- mice c) the aortic expression of Group V and Group X sPLA2 mRNA is increased in apoE-/- mice infused with Angll; d) these isozymes are expressed by macrophages; e) these isozymes have been implicated in cyclooxygenase 2 (COX-2)-dependent prostanoid production; and f) mice treated with a COX-2-selective inhibitor have significantly reduced AAAs in response to chronic Angll infusion. To test this hypothesis, we propose to identitify specific sPLA2(s) mediating AAA progression, and define the relative contribution of leukocyte expression of these sPLA2 isozymes in its pathogenic effect (Specific Aim 1); define the relative contribution of systemic versus leukocyte-expressed Group IIA sPLA2 in mediating Angll-induced AAAs (Specific Aim 2); and determine whether the pathogenic effect of sPLA2 is dependent on COX-2 activity (Specific Aim 3). These studies hold the potential to identify a new target for AAA intervention.