microRNA21调控TGFβ1-Smad信号通路介导放射性心脏损伤的机制研究

Previous results suggested that TGFβ1 is a very important cytokine in the process of cardiac fibrosis. The expression of TGFβ1 increases as well as the development of cardiac fibrosis. The study of TGFβ1-Smad pathway in cardiac fibrosis showed that the expression of Smad2/3 increased while Smad7 decreased in fibrotic tissue. When the process of fibosis had been inhibited, the expression of Smad2/3 decreased while Smad7 increased in the irradiated cardiac tissue. MicroRNA array of irradiated rat heart showed that miR-21 had the association with cardiac fibrosis and TargetScan predicts that Smad7 is the main target gene of miR-21. After irradiation to the cardiac fibroblast, the expression of miR-21 increased, while pSmad7 was significantly inhibited. The study of rat infarction heart failure model also showed an increase of Smad2/3 and a decrease of Smad7 in fibrotic tissue, while an increase of Smad7 in viable cardiac tissue. At the meantime, the expression of miR-21 increased in fibrotic tissue and decreased in viable cardiac tissue. These results suggested that miR-21 had a significant relationship with Smad7, and miR-21 may regulate the cardiac fibrotic process of cardiac fibrosis by inhibiting the protective function of Smad7.The purpose of this study is to investigate and validate the relationship between miR-21 and TGFβ1-Smads signaling pathway on radiation induced heart fibrosis.

前期研究提示TGFβ1是大鼠放射性心脏损伤重要的细胞因子。在TGFβ1-Smad信号通路的研究中发现，Smad2/3在受照射心脏组织的表达持续升高， Smad7的表达明显下降;在纤维化受抑制期Smad2/3明显下降而Smad7则持续上升。miRNA分子筛选结果提示miR-21与心脏纤维化发生有关，生物信息预测软件提示Smad7是miR-21的靶标。大鼠心脏成纤维细胞受照后，miR-21明显升高并抑制pSmad7蛋白表达。大鼠心梗后心衰模型也显示，瘢痕组织中pSmad3及pSmad2的表达升高，pSmad7的表达下降；存活心肌中pSmad7的表达则较瘢痕组织明显上升，同时miR-21的表达在瘢痕组织中上升而在存活心肌中下降。miR-21可能通过抑制Smad7的功能调控放射性心脏损伤的发生发展。本研究拟对miR-21与Smad7相互关系进行验证，探索应用miR-21减轻放射性心脏损伤的可能性。

基础研究中microRNA分子筛选的结果提示miR-21与心脏纤维化发生有关，生物信息学预测软件提示Smad7是microRNA21作用的靶标。在初步确认分子生物靶标的基础上，我们希望寻找与患者心脏损伤相关的临床检查及检验方法，以促进基础研究结果的转化应用。据国外报道远期的心脏毒性可能是食管癌患者根治性放疗后的主要死因，选择合适的评估方法非常重要。我们的研究提示，磁共振由于可以集形态、功能集细胞生物学检查为一体，可以在现有检查基础之上，进一步精确评估食管肿瘤对治疗的反应以及心脏在治疗后的功能改变。此外，我们还对接受不同根治性治疗手段的食管癌患者进行配对研究，发现与国外结果不同，我国食管癌患者的心脏毒性以急性改变为主，且与采用的治疗手段关系不大，提示在不同种族及不同生活习惯的食管癌人群中，其心脏毒性的表型可有较大的差别。同时我们也发现，积极的营养干预和管理，有可能进一步控制我国食管癌患者的急性毒性发生概率。利用分子生物靶标结合临床检测及管理手段，有可能减少食管癌患者心脏损伤的发生机会，对急性损伤的管理在我国食管癌患者的治疗中可能更为重要。