The role of PON2 and PON3 proteins in Atherosclerosis

描述(申请人提供)：在人类和动物模型中的许多病理生理学观察导致假设动脉粥样硬化是一种多因素的慢性炎症性疾病，血浆低密度脂蛋白水平和高低密度脂蛋白水平是疾病的强烈预测因素。动脉粥样硬化是一种大动脉疾病，是冠心病和中风的主要原因。低密度脂蛋白的氧化被认为是动脉粥样硬化病变发展过程中的一个重要过程。氧化型低密度脂蛋白的致炎成分是各种氧化型磷脂，由氧化型不饱和脂肪酸的断裂和重排产生。高密度脂蛋白和高密度脂蛋白相关酶具有抗动脉粥样硬化的特性，这部分是由于它们对氧化的低密度脂蛋白失活。尽管遗传和生化研究证实了高密度脂蛋白相关蛋白对氧磷酶-1(PON1)的抗动脉粥样硬化作用，但PON家族蛋白PON1、PON2和PON3的生理功能尚不清楚。根据我们的初步发现，我们假设PON2和PON3蛋白抑制氧化磷脂在低密度脂蛋白中的积累，保护动脉壁细胞免受来自活性氧物种(ROS)和氧化磷脂的氧化应激，并防止动脉粥样硬化病变的发展。在这一应用中，我们建议：1)表征PON_2和PON_3蛋白的生化和酶性质；2)在高密度脂蛋白和高胆固醇血症动物模型中测定PON_2和PON_3蛋白的细胞定位、酶活性产物和表达水平；3)建立转基因小鼠和基因敲除小鼠，以确定PON_2和PON_3蛋白的生理功能以及PON_2和PON_3在动脉粥样硬化中的作用；以及4)鉴定和鉴定与PON_2和PON_3相互作用的蛋白质，以描述PON_2和PON_3蛋白的生物底物。了解PON蛋白的生物学和功能将为发现新的治疗药物对抗动脉粥样硬化和其他炎症性疾病铺平道路。

DESCRIPTION (provided by applicant): A number of pathophysiological observations in humans and animal models led to the hypothesis that atherosclerosis, a disease of the large arteries that is the primary cause of coronary heart disease (CHD) and stroke, is a multifactorial chronic inflammatory disease in which low plasma levels of HDL and high plasma levels of LDL, are a strong predictor of the condition. LDL oxidation is considered to be an essential process in the development of atherosclerotic lesions. The pro-inflammatory constituents of oxidized LDL are various oxidized phospholipids resulting from the scission and rearrangement of oxidized, unsaturated fatty acids. HDL and HDL-associated enzymes possess anti-atherogenic properties that are due, in part, to their inactivation of oxidized LDL. Although genetic and biochemical studies demonstrated anti-atherogenic role for paraoxanase-1 (PON1), a HDL associated protein, to date, the physiological functions of PON family of proteins; PON1, PON2 and PON3, remain unknown. Based on our preliminary findings, we hypothesize that PON2 and PON3 proteins inhibit the accumulation of oxidized phospholipids in LDL, protect artery wall cells against oxidative stress from reactive oxygen species (ROS) and oxidized phospholipids, and prevent the development of atherosclerotic lesions. In this application, we propose to i) characterize the biochemical and enzymatic properties of PON2 and PON3 proteins, ii) determine cellular localization, products of enzyme activity and the expression levels of PON2 and PON3 proteins in HDL and hyperchloesterolemic animal models, iii) develop transgenic mice and knockout mice to determine the physiological function of PON2 and PON3 proteins as well as the role of PON2 and PON3 in atherosclerosis, and iv) identify and characterize proteins that interact with PON2 and PON3 to delineate the biological substrates of PON2 and PON3 proteins. Understanding the biology and function of the PON proteins will pave way for the discovery of novel therapeutic agents in the fight against atherosclerosis and other inflammatory diseases.