LncRNA-Cox2调控的炎症反应在放射性心脏血管内皮细胞损伤中的作用及机制研究

Radiation induced heart injury seriously affects the quality of life and survival time of chest radiotherapy patients. Studies have shown that vascular injury plays an important role in radiation induced heart injury, but the molecular mechanism of the injury is still poorly understood. Our previous study found that expression of LncRNA-Cox2 and many other inflammation related factors was significantly upregulated after mouse heart was irradiated, associated with vascular endothelial inflammatory response, closed gaps and decreased microvascular density. New research suggests that LncRNA-Cox2 plays an important role in mediating cellular immune response. Accordingly, we speculate that radiation induced LncRNA-Cox2 expression regulates inflammatory gene transcription and influences radioactive heart vascular endothelial cell injury. This study will clarify the effect of LncRNA-Cox2 in radioactive heart vascular endothelial cell injury at the levels of molecules, cells, tissues and whole animals. It will explore the molecular mechanisms of LncRNA-Cox2-related inflammation and LncRNA-Cox2-related inflammatory radioactive heart vascular endothelial cell injury. The study will generate new ideas for prevention and control of radiation induced heart injury.

放射性心脏损伤严重影响胸部肿瘤放疗患者的生活质量及生存时间，血管内皮细胞损伤是放射性心脏损伤的关键，但其损伤的分子机制尚不清楚。我们前期研究发现，小鼠心脏受放射线照射后LncRNA-Cox2及炎症相关基因显著表达上调，伴随血管内皮持续炎症反应、管腔狭窄、微血管密度降低。最新研究表明LncRNA-Cox2在介导细胞炎症反应中起中心重要作用。据此我们提出假说：放射线诱导LncRNA-Cox2表达，促进炎症相关基因转录，产生局部炎症反应，影响放射性心脏血管内皮细胞损伤。本课题拟从分子、细胞、组织及动物水平等多层次明确LncRNA-Cox2在放射性心脏血管内皮细胞损伤中的作用；探讨LncRNA-Cox2对炎症相关基因的调控机制；揭示LncRNA-Cox2通过免疫调控影响放射性心脏血管内皮细胞损伤的机制。本研究将从LncRNA这个新视点探讨放射性心脏损的发生机制，为放射性心脏损的防治提供新的思路。

胸部放疗增加了放射性心脏损伤(RIHD)发生风险；然而，RIHD发生分子机制还不完全清楚。本研究目的是利用高通量蛋白质组学研究辐射对小鼠心脏的影响。选用雄性C57BL/6J小鼠，用16Gy高能X射线全心照射建立小鼠RIHD模型，照射后5个月使用心脏超声心动图、BNP、H&E和Masson染色证实心脏损伤。照射5个月后的小鼠和假照射小鼠的心尖组织进行蛋白质组学分析。差异表达最显著的蛋白质集中在“心脏纤维化”和“能量代谢”。IHC和Western blotting结果证实心肌纤维化（细胞外基质蛋白，如1型胶原α1链、III型α1链、波形蛋白和CCTc结合因子）和能量代谢相关蛋白（如脂肪酸合成酶和溶质载体家族25成员1），在电离辐射后表达上调。此外，心肌线粒体内膜受到损伤，ATP水平降低，心肌组织中乳酸积聚。这些结果表明，高剂量电离辐射可导致小鼠心脏结构重塑、功能损伤和纤维化改变。因此，辐射诱导的心肌组织线粒体损伤和代谢改变可能是RIHD的发病机制之一，为预防和治疗放射性心脏损伤提供新的方向。