Specific Secretory Phospholipase A2 Isozymes Promote Aneurysm Formation

特异性分泌型磷脂酶 A2 同工酶促进动脉瘤形成

• 批准号: 7160754
• 负责人: Nancy R Webb
• 金额: $ 31.44万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7160754
• 关键词: abdomen; angiotensin II; aorta aneurysm; cardiovascular disorder risk; cell migration; disease /disorder model; enzyme activity; gene expression; genetic susceptibility; genetically modified animals; inflammation; isozymes; laboratory mouse; macrophage; pathologic process; phospholipase A2; prostaglandin endoperoxide synthase; protein localization

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.

分泌型磷脂酶A2酶(sPLA2‘S)，特别是HA、V和X群 亚型，与多种炎症性疾病有关。我们提供证据证明 SPLA2在小鼠腹主动脉瘤(AAA)形成中起促进作用 血管疾病。具有广泛特异性的sPLA2抑制剂可显著降低发病率和严重程度。 血管紧张素II(Ang11)诱导apoE-/-小鼠AAA的作用。此外，表达人类基因的转基因小鼠 与非转基因小鼠相比，IIA组sPLA2对Ang11诱导的AAA的易感性增加。 该提议的中心假设是IIA组、V组和/或X组sPLA2由 巨噬细胞通过促进AAA的局部释放促进AAA的形成 炎性前列腺素。这一假设是基于已公布的数据和我们自己的初步发现： A)巨噬细胞渗入腹主动脉内层是腹主动脉硬化的早期事件；b)V组 和X组sPLA2蛋白在apoE-/-小鼠AAA中表达c)V组和 输注Ang11的apoE-/-小鼠X组sPLA2基因表达增加；d)这些同工酶通过 巨噬细胞；e)这些同工酶与环氧合酶2(COX-2)依赖的前列腺素有关 生产；和f)用COX-2选择性抑制剂处理的小鼠显著减少了AAA的反应 到慢性天使输液。为了验证这一假说，我们建议确定介导AAA的特定sPLA2(S) 进展，并确定这些sPLA2同工酶在ITS中白细胞表达的相对贡献 致病效应(特定目标1)；定义全身性与白细胞表达的相对贡献 IIA组sPLA2在介导Ang11诱导的AAA(特异性靶点2)中的作用；并确定致病因子 SPLA2的作用依赖于COX-2活性(特异靶3)。这些研究有可能确定 AAA干预的新靶点。