β-arrestin2在高糖诱导内皮祖细胞功能障碍中的调节作用及机制

High glucose-induced endothelial progenitor cell (EPC) dysfunction is one of the pathophysiological processes of myocardial infarction in diabetes, which represents angiogenesis and paracrine impairment. Searching for a critical gene that mediates high glucose-induced EPC dysfunction is very helpful to improve EPC function. β-arrestin2, one of the multifunctional adaptor proteins, mediates G protein-coupled receptor signaling as well as the transduction of other signaling molecules in the cytosol and regulates the processes of cell migration and apoptosis. We previously found out that the expression of β-arrestin2 on EPC was decreased in high glucose condition while overexpression of β-arrestin2 promoted EPC migration and the expression of angiogenic cytokines. However, the underlying mechanisms remain unclear. In this study, we will investigate the effects and mechanisms of β-arrestin2 on EPC migration, apoptosis, tube formation and angiogenic cytokines secretion in high glucose-induced EPC dysfunction model via overexpressing or silencing β-arrestin2 on EPC. We will transplant gene-modified EPC in myocardial infarction model in rat with type 2 diabetes and clarify its effects on the density of capillary, infarct size and cardiac function, providing new experimental evidences and targets for clinical intervention for EPC dysfunction in diabetes.

高糖诱导内皮祖细胞(EPC)功能障碍是糖尿病合并心肌梗死的病理过程之一,主要表现为“血管新生”以及“旁分泌”受损。寻找介导高糖损伤EPC的关键基因具有重要意义。β- arrestin2作为一种支架蛋白除了介导G蛋白偶联受体信号通路外,还参与细胞内多种信号分子的转导,调控细胞迁移、凋亡等过程。我们前期研究发现,高糖刺激后EPC中β-arrestin2表达降低,而过表达β-arrestin2能够提高EPC迁移以及促血管新生因子表达,但其具体作用机制尚未清楚。本项目拟应用高糖诱导EPC损伤模型,通过过表达或沉默β-arrestin2基因,探讨β- arrestin2对EPC迁移、凋亡、体外血管形成以及分泌促血管新生因子等功能的影响及机制;通过在糖尿病大鼠心肌梗死模型中移植基因修饰的EPC,观察其对新生血管密度、梗死面积及心脏功能的影响,为寻找糖尿病EPC损害的防治靶点提供理论依据及实验基础。

高糖诱导内皮祖细胞(EPC)功能障碍是糖尿病合并心肌梗死的病理过程之一,主要表现为“血管新生”以及“旁分泌”受损。寻找介导高糖损伤EPC的关键基因具有重要意义。β- arrestin2作为一种支架蛋白除了介导G蛋白偶联受体信号通路外,还参与细胞内多种信号分子的转导,调控细胞迁移、凋亡等过程。我们前期研究发现,高糖刺激后EPC中β-arrestin2表达降低,而过表达β-arrestin2能够提高EPC迁移以及促血管新生因子表达,但其具体作用机制尚未清楚。综上原因，我们开展本项目研究并获得相关结果：第一，在高糖诱导EPC功能异常中，β-arrestin2具有双重调控作用，既能调控EPC增殖、迁移、体外血管形成等直接促血管新生相关功能，又能促进EPC分泌促血管新生因子。第二，在高糖环境下, 与CXCR4结合的β-arrestin2减少，SDF-1/CXCR4介导的PI3K/Akt活性降低，导致EPC迁移、增殖减弱、凋亡增加，这是高糖诱导EPC“血管新生”功能障碍的主要分子机制；在高糖环境下，β-arrestin2下调引起Raf-1、MEK1及ERK磷酸化障碍，EPC分泌促血管新生因子VEGF、IL-8减少，这是EPC“旁分泌”功能障碍的主要分子机制。第三，上调β-arrestin2表达的EPC可有效抵抗高血糖造成的EPC损伤，促进糖尿病大鼠心肌梗死后心功能的恢复。本研究项目的科学意义在于进一步阐明高糖损伤EPC的机制，为寻找糖尿病EPC损害的防治靶点提供理论依据及实验基础。