The role of PON-2 and PON3 proteins in atherosclerosis

描述(申请人提供)：对氧磷酶(PON)基因家族由PON1、PON2和PONS三个家族成员组成。PON基因参与了包括动脉粥样硬化在内的多种炎症性疾病的发病过程。这三种PON蛋白都具有抗氧化性和内酯酶活性，但PON蛋白的生理底物及其作用机制尚不清楚。我们的长期目标是了解PON2和PONS蛋白在生理和疾病中的作用。在上一次资助期间，我们建立了PON2和PONS基因的转基因/敲除小鼠模型，并为PON2和PONS蛋白的抗动脉粥样硬化功能提供了第一个体内证据。我们还证明了氧化磷脂或脂质过氧化产物不是纯化PON酶的直接底物，这表明导致动脉粥样硬化的氧化磷脂的直接失活不是PON蛋白作用的关键机制。我们认为PON蛋白的抗动脉粥样硬化活性是由于它们对一类参与低密度脂蛋白氧化的未知促炎性脂内酯的活性所致。有趣的是，在一个非常令人兴奋的事件中，我们最近发现PON2和PONS蛋白降解革兰氏阴性细菌密度依赖的敏感分子，称为酰基高丝氨酸内酯(AHL)，参与革兰氏阴性毒力。阿尔是脂内酯类药物。由于革兰氏阴性毒力在包括动脉粥样硬化在内的炎症性疾病的病理中得到了很好的证实，我们认为对由革兰氏阴性毒力因子(如AHLS)和其他未知的促炎性内酯介导的促炎途径的保护是PON蛋白的关键生理功能。我们将在PON2和PONS转基因/基因敲除小鼠模型中验证这一假设，目的有两个：1)研究PON2和PONS在缓解动脉粥样硬化发展中的分子机制和功能；2)确定PON2和PONS是否在宿主防御促炎性群体感应分子和革兰氏阴性细菌感染中发挥作用。我们推测PON2和PONS是一类新的内酯酶，可以降解1)与动脉粥样硬化相关的致动脉粥样硬化脂内酯，以及2)与革兰氏阴性菌相关的促炎性酰基高丝氨酸内酯，从而阻止炎症性疾病的发生。

DESCRIPTION (provided by applicant): The paraoxonase (PON) gene family consists of three family members, PON1, PON2 and PONS. PON genes are implicated in the pathogenesis of several inflammatory diseases including atherosclerosis. All three PON proteins possess antioxidant properties and lactonase activities; however, the physiological substrates for PON proteins and their mechanism of action remain unknown. Our long-term goal is to understand the role of PON2 and PONS proteins in physiology and disease. During the last grant period, we have developed transgenic/knockout mouse models for PON2 and PONS genes, and provided the first in vivo evidence for the anti-atherogenic functions of PON2 and PONS proteins. We have also demonstrated that oxidized phospholipids or lipid peroxidation products are not direct substrates for purified PON enzymes, suggesting that direct inactivation of atherogenic oxidized phospholipids is not a key mechanism of action of PON proteins. We propose that the anti-atherogenic activities of PON proteins are a result of their activity towards a class of unidentified pro-inflammatory lipo-lactones that participate in LDL oxidation. Interestingly, in a very exciting turn of events, we recently discovered that PON2 and PONS proteins degrade gram-negative bacterial density-dependent sensing molecules termed acyl homoserine lactones (AHL) involved in gram-negative virulence. AHLs are lipo-lactones. Since gram-negative virulence is well established in the pathology of inflammatory diseases, including atherosclerosis, we propose that protection against pro-inflammatory pathways mediated by gram-negative virulence factors, such as AHLs, and other unidentified pro-inflammatory lipo-lactones, is a key physiological function of PON proteins. We will test this hypothesis in PON2 and PONS transgenic/knockout mouse models under two specific aims to 1) investigate the molecular mechanisms and function of PON2 and PONS in mitigating the development of atherosclerosis and 2) determine whether PON2 and PONS play a role in host defense against pro-inflammatory quorum sensing molecules and gram-negative bacterial infection. We hypothesize that PON2 and PONS are a novel class of lactonases that degrade i) atherogenic lipo-lactones associated with atherosclerosis, and ii) pro-inflammatory acyl homoserine lactones associated with gram-negative bacteria, thus preventing the pathogenesis of inflammatory diseases.