心肌细胞缺氧损伤时内源性多肽PDFC的作用及机制研究

PDFC is an endogenous peptide identified by peptidomics techniques. Its expression in mice cardiomuocytes showed significant difference after hypoxia without any function report. Further study revealed that PDFC could reduce the apoptosis of P19 cells after hypoxia; The expression of myocardial cell marker in anoxic P19 cells was elevated after treated by PDFC，reminded us that maybe PDFC could protect P19 cells after hypoxia by reducing apoptosis; Furthermore, we found the mailnly proteins in PI3K/AKT signaling pathway(AKT-473/308、P-PRAS40) in anoxic P19 cells was activated after treated by PDFC, suggested us that PDFC may play biological role by regulating PI3K/AKT signaling pathway. In this study, we verify its effect in cultured cardiomyocytes and animal models after hypoxia. To elucidate the molecular mechanism of regulation of PI3K/AKT signaling pathway, physical methods, rescue experiments are carried out. To assess the feasibility of PDFC in clinical treatment of perinatal hypoxic myocardial injury, we explore its toxicity and side effects, pharmacokinetics, tissue distribution and function after chemical modification. These studies may provide a new opportunity for the treatment of perinatal hypoxic myocardial injury.

PDFC是我们借助多肽组学发现的、在缺氧情况下心肌细胞内表达差异显著、功能未知的内源性多肽。前期发现，经PDFC处理的缺氧情况下的P19细胞，其凋亡细胞数量较未处理的缺氧组明显减少，且其心肌细胞标志蛋白表达水平亦明显升高，提示PDFC肽对缺氧导致的心肌细胞损伤具有潜在的保护作用。同时，我们发现PI3K/AKT信号通路中的主要蛋白（如AKT-473/308、P-PRAS40等），在PDFC处理后缺氧的P19细胞中表达明显上调，提示PDFC肽可能通过调控PI3K/AKT信号通路而发挥生物学作用。本研究拟评估PDFC肽在缺氧情况下对体外培养的小鼠心肌细胞及围产期活体小鼠心肌细胞损伤的保护作用；借助物理学方法、挽救实验策略，阐明其调控PI3K/AKT信号通路的分子机制；通过揭示其毒副作用、药代动力学、组织分布特征、化学修饰后的功能，评估PDFC作为围产期缺氧导致的心肌细胞损伤治疗手段的可行性。