尿酸通过修饰蛋白作用诱导内皮功能紊乱及花色苷的干预作用机制研究

Cardiovascular disease(CVD) , one of the major causes of morbidity and mortality worldwide, had become a public health problem in China during the past few decades. Atherosclerosis(AS) is the basic pathophysiology of CVD, and endothelial dysfucion is the primary and pathlogy stages of AS. Previous studies have showed that UA level is an important prognostic risk marker for CVD and hyperuric acid plays a crucial role in the pathophysiology of AS. Oxidative stress contribute substantially to the development of AS. Serum levels of uric acid are positively correlated with obesity AS. However, there is a lack of evidence to known its mechanism. We will combine population–based studies with laboratory studies in this study. After clarifing the high glucose would induced the advanced glycation end products(AGEs) on endotheil cells by protein modified UA，we will conduct animal model to evalulation about endothelial dysfuction and molecular mechanism by protien modefied UA. Meanwhile, we will confirm the anthocyanins have a role preventing for the protien modification UA in mouse model by acivated the signal with AGE and its receptor(AGE-RAGE)pathway, from the molecular, cell, tissue, individual and population ,etc. This study to provide theretical and experimental basis for UA impaird endothial fuction, to further enriched the theoretical and experimental basis for development of anthocyanins, and to provide new ideas for establishment of HUA intervention strategies.

内皮功能紊乱是动脉粥样硬化（AS）发生发展的起始因素，研究已证实高尿酸血症（HUA）可通过氧化应激反应来诱导内皮功能紊乱，但具体机制尚不十分清楚。本课题拟将实验室研究和人群研究相结合，在明确HUA在高糖环境下可诱导产生糖基化终产物的基础上，利用细胞模型，观察蛋白修饰的UA对内皮功能的影响及可能机制；同时，以植物界分布最为广泛的花色苷（anthocyanins）作为受试物，明确花色苷具有干预蛋白修饰的尿酸致内皮损伤的作用及可能机制，在病理生理、组织细胞形态、细胞因子表达和分泌等多个层次探讨花色苷延缓动脉粥样硬化。研究将为HUA作为冠心病独立危险因素奠定理论基础，为花色苷抗AS的临床应用及营养膳食防治奠定理论基础。

尿酸是否是冠心病的危险因素，目前仍无定论。内皮功能受损是动脉粥样硬化引起的冠心病的起始因素。本课题首先从流行病学角度证实尿酸作为冠心病的危险因素的科学依据确实可信，并且与肾功能有密切关系。根据预期研究目标建立了蛋白修饰的UA诱导的内皮细胞功能紊乱模型，结果证实，蛋白修饰的UA具有时间和剂量依赖性诱导内皮细胞凋亡、坏死和增生，并激活了AGE-RAGE信号通路的磷酸化，这可能是尿酸促进动脉粥样硬化的一个新的可能机制。.本项目根据预期成功招募了冠心病合并高尿酸血症的患者，受试物为植物化学物花色苷提取物，进行6个月的随访研究，探讨了植物化学物-花色苷对内皮功能，炎症因子的影响，从而具有延缓和预防动脉粥样硬化的发生和发展。研究结果真实可信，实验方案科学合理，经过本研究，为尿酸作为冠心病独立危险因素奠定理论基础,为花色苷临床应用及营养膳食防治奠定理论基础。