PML蛋白调控心肌纤维化作用及其分子机制

Promyelocytic leukemia protein (PML) has been identified and proved to be localized in both cytoplasm (c-PML) and nuclear. Notably, SUMOylation form of nuclear PML protein is the major component that forms the PML-nuclear bodies (PML-NBs), which may have important biological functions. However, the role of PML in major cardiac diseases has not been identified. Our previous studies and other studies have demonstrated that arsenic trioxide (As2O3, ATO), an effective therapeutic agent for the treatment of acute promyelocytic leukemia (APL), can up-regulate the expression of transforming growth factor-β (TGF-β) and induce interstitial myocardial fibrosis. PML is a direct target of ATO, and the SUMOylation of PML and formation of PML-NBs are promoted by ATO. Although hardly unknown but these results strongly suggests that PML is a key regulator of cardiac fibrosis. Our preliminary data have shown that high abundance of PML are respectively expressed in both cardiomyocytes and cardiac fibroblasts. The present proposal was designed to determine the expression changes of PMLs including PML-NBs and c-PML during cardiac fibrosis; to establish the molecular networks by which PMLs regulate cardiac fibrosis, including the signaling of PML-NBs and Pin1 regulating TGF-β1, and interactions between c-PML and Smad2/3; and to identify and compare the roles and efficacies of various PMLI~PMLVII isoforms in the regulating myocardial remodeling. The present proposal will firstly demonstrate that PML is a critical regulator in myocardial remodeling process, and will certainly expand our understanding on the roles of PMLs in regulating cardiac fibrosis and provide a novel intervention target.

早幼粒细胞白血病蛋白(PML)，存在于细胞浆(c-PML)和细胞核中，细胞核PML可发生SUMO化修饰形成PML核体(PML-NBs)发挥重要生物学功能，然而其在重大心脏疾病中的作用尚不清楚。我们和已有的研究证实，一种治疗早幼粒细胞白血病最有效药物三氧化二砷(ATO)可上调TGF-β1表达并诱导心肌纤维化的发生，而PML为ATO直接作用靶点可被SUMO化并形成PML-NBs，预示PML可能为心肌纤维化的重要调控分子。本课题在证实PML在心脏高丰度表达的基础上，揭示PML-NBs和c-PML在心肌纤维化中的变化规律；建立PML-NBs通过Pin1调控TGF-β1的表达以及c-PML与Smad2/3共偶联调控心肌纤维化分子机制；确定编码c-PML的候选PML异构体类型；探索PML是否为抗心肌纤维化药物治疗靶点。该研究将首次探讨PML在心肌纤维化中的作用，并为重大心脏疾病提供新理论和干预靶点。

本项目按照研究计划如期开展，达到了既定研究目标，取得了创新性研究成果：在心脏成纤维细胞中，早幼粒细胞白血病蛋白（Promyelocytic leukemia protein, PML）的SUMO化修饰参与心肌纤维化的调节；其主要机制为在外源性刺激因素（如压力负荷、TGF-β1、AngII、三氧化二砷）作用下，PML SUMO化修饰增强，其核体PML-NBs增加， PML-NBs招募Pin1，促进TGF-β1表达，进一步激活TGF-β信号通路；干预PML SUMO化进程，可影响心肌纤维化和心脏功能；我们也探讨了小分子抑制剂干预心肌纤维化的可能性。本项目为全面理解PML在心肌纤维化中的作用做了有益的探索。