Non-COX Arachidonic Acid Metabolites and Angiogenesis

组织损伤后的炎症被认为在包括动脉粥样硬化、癌症和视网膜病变在内的各种疾病的发生和发展中起着重要作用。磷脂酶A2(PLA2)是一组分解磷脂产生花生四烯酸和溶血磷脂的酶，与炎症有关。动脉粥样硬化进展的主要事件之一是血管生成。血管内皮细胞(EC)迁移和增殖是血管生成的关键事件。新的证据表明，PLA2、花生四烯酸及其二十烷基类代谢物在细胞迁移、增殖和凋亡的调节中发挥作用。此外，最近使用非类固醇抗炎药的研究揭示了二十烷类化合物在血管生成中的潜在作用。基于这一认识，我们假设二十烷类化合物，特别是花生四烯酸的脂氧合酶-单加氧酶代谢产物，在血管生成中发挥重要作用，从而影响动脉粥样硬化的发病机制。为了测试二十烷类化合物在血管生成中的作用，我们将致力于以下四个具体目标：1.鉴定人微血管内皮细胞(HMVEC)产生的二十烷类化合物，并利用体外和体内模型确定它们对血管生成的影响。2.探讨血管生成二十烷类化合物对人脐静脉内皮细胞迁移和增殖的影响。3.探讨Jak/STAT和PI3K/Akt信号通路在二十烷基类药物诱导的血管内皮细胞迁移和增殖中的作用。4.鉴定二十烷基三烯类化合物诱导血管生成的效应分子，并研究其调控血管内皮细胞和血管平滑肌细胞表达的机制。这一建议的结果将为鉴定特定的血管生成二十烷类化合物和阐明这些脂质分子刺激血管生成的潜在机制提供新的信息。这些知识反过来可能有助于开发预防动脉粥样硬化等疾病进展的治疗方法。

Inflammation that follows tissue injury is believed to be important in the initiation and progression of various diseases including, atherosclerosis, cancer, and retinopathy. Phospholipase A2s (PLA2s), a group of enzymes that breakdown phospholipids generating arachidonic acid and lysophospholipids have been implicated in inflammation. One of the major events underlying the progression of atherosclerosis is angiogenesis. Endothelial cell (EC) migration and proliferation are critical events in angiogenesis. Emerging evidence suggests that PLA2, arachidonic acid and its eicosanoid metabolites play a role in the regulation of cell migration, proliferation, and apoptosis. In addition, recent investigations using nonsteroidal anti-inflammatory drugs reveal a potential role for eicosanoids in angiogenesis. Based on this knowledge, we hypothesize that eicosanoids, particularly the lipoxygenase-monooxygenase metabolites of arachidonic acid, play an important role in angiogenesis and thereby influence the pathogenesis of atherosclerosis. To test the role of eicosanoids in angiogenesis we will address the following four specific aims: 1. To identify eicosanoids produced in human microvascular endothelial cells (HMVEC) and determine their effects on angiogenesis using in vitro and in vivo models. 2. To determine the effects of angiogenic eicosanoids on HMVEC migration and proliferation. 3. To test the role of the Jak/STAT and PI3K/Akt pathways in angiogenic eicosanoid-induced HMVEC migration and proliferation. 4. To identify the effector molecules of eicosanoid-induced angiogenesis and study the mechanisms underlying their regulation of expression in HMVEC and vascular smooth muscle cells. The results of this proposal will provide novel information on the identification of specific angiogenic eicosanoids and on elucidation of the underlying mechanisms by which these lipid molecules stimulate angiogenesis. Such knowledge, in turn, could be useful in developing therapeutics in the prevention of progression of diseases such as atherosclerosis.