Atheroprotective Mechanisms of Ursolic Acid and Related Phytochemicals

描述（由申请人提供）：包括肥胖、血脂异常和糖尿病在内的代谢性疾病似乎与单核细胞功能障碍相关，但体内单核细胞功能障碍的分子机制仍知之甚少。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活化，单核细胞功能障碍是动脉粥样硬化发展和进展中的关键和限速步骤。我们现在已经发现，膳食补充熊果酸（一种具有抗炎特性的三萜类化合物）可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。此外，我们还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中的关键步骤，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阻止单核细胞中代谢应激诱导的蛋白-S-谷胱甘肽化、丝裂原活化蛋白激酶磷酸酶（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，并确定熊果酸抗动脉粥样硬化特性的结构特征和单核细胞保护的分子机制，我们提出了两个具体目标：具体目标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。具体目标2：确定膳食熊果酸及其类似物预防动脉粥样硬化的机制。本申请的目的是鉴定熊果酸和结构上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.