Atheroprotective Mechanisms of Ursolic Acid and Related Phytochemicals

描述（由申请人提供）：代谢紊乱包括肥胖、血脂异常和糖尿病似乎与单核细胞功能障碍有关，但体内单核细胞功能障碍的分子机制尚不清楚。我们最近的研究表明，代谢应激促进单核细胞对趋化因子反应的失调和过度激活，单核细胞功能障碍是动脉粥样硬化发生和发展的关键和限速步骤。我们现在已经发现，在饮食中补充熊果酸（一种具有抗炎特性的三萜），可以减轻单核细胞功能障碍和巨噬细胞募集，并保护糖尿病小鼠免受动脉粥样硬化的影响。此外，我们已经阐明了高胆固醇血症和高血糖促进单核细胞功能障碍的新机制的关键步骤，并确定了熊果酸及其类似物抗动脉粥样硬化和抗炎活性的几个新的潜在靶点。基于这些数据，我们假设熊果酸通过防止代谢应激诱导的单核细胞中蛋白- s-谷胱甘肽化、丝裂原激活的蛋白激酶磷酸酶（MKP）的失活和降解来保护单核细胞功能障碍和动脉粥样硬化。为了验证我们的假设，并确定熊果酸负责抗动脉粥样硬化特性的结构特征和参与单核细胞保护的分子机制，我们提出了两个特定目标：特定目标1：确定熊果酸及其类似物预防代谢应激诱导的单核细胞功能障碍的保护机制。具体目的2：确定膳食熊果酸及其类似物预防动脉粥样硬化的机制。本应用程序的目的是确定熊果酸和结构相关的植物化学物质的动脉粥样硬化保护机制。

DESCRIPTION (provided by applicant): Metabolic disorders including obesity, dyslipidemia and diabetes appear to be associated with monocyte dysfunction, yet the molecular mechanisms underlying monocyte dysfunction in vivo are only poorly understood. Our recent studies showed that metabolic stress promotes the dysregulation and hyper-activation of monocyte responses to chemokines and that monocyte dysfunction is a critical and rate-limiting step in the development and progression of atherosclerosis. We have now found that dietary supplementation with ursolic acid, a triterpenoid with anti-inflammatory properties, attenuate monocyte dysfunction and macrophage recruitment and protects diabetic mice from atherosclerosis. In addition, we have elucidated key steps in a novel mechanism through which hypercholesterolemia and hyperglycemia promote monocyte dysfunction, and have identified several novel potential targets for the anti-atherogenic and anti-inflammatory activity of ursolic acid and its analogues. Based on these data, we hypothesize that ursolic acid protects against monocyte dysfunction and atherosclerosis by preventing metabolic stress-induced protein-S-glutathionylation, inactivation and degradation of mitogen-activated protein kinase phosphatases (MKP) in monocytes. To test our hypothesis and to identify both the structural features of ursolic acid responsible for the anti- atherogenic properties and the molecular mechanisms involved in monocyte protection, we propose two Specific Aims: Specific Aim 1: To determine the protective mechanisms through which ursolic acid and its analogues prevent monocyte dysfunction induced by metabolic stress. Specific Aim 2: To determine the mechanism by which dietary ursolic acid and its analogues protect against atherosclerosis. The goal of this application is to identify the atheroprotective mechanism(s) of ursolic acid and structurally related phytochemicals.