PDCD4基因影响小鼠心房重构机制的研究

Atrial Fibrillation (AF), which is one of the most common arrhythmia, has become a heated discussion in its nosogenesis. The occurrence and maintenance of AF are accompanied by atrial electrical remodeling and structural reconstruction, meanwhile the inflammatory response is regarded as a substantial procedure which results in the AF. And now the scholars home and abroad hold that PDCD4 (one of the tumor suppressor genes), as a Proinflammatory factor, plays an important role in the inflammatory response while it is uncertain that the factor has impact on atrial remodeling according to the inflammatory response. Based on the above research background, we hypothesized that PDCD4 gene may be associated with atrial remodeling. To prove this conjecture, we proposed to build PDCD4 overexpression transgenic and PDCD4 gene knockout in mouse models,choose the same age mice which were genetically normal as a control group, and observe two groups of mice serum inflammatory cytokines expression, atrial effective refractory period change and the atrial muscle fiber levels, thus exploring the effect of high expression or deletion of PDCD4 on inflammation and atrial electrical remodeling and structure reconstruction in mouse models.In order to elucidate the high expression or deletion of PDCD4 gene, the inflammatory response in mice was enhanced or weakened, which caused the changes of atrial electrical reconfiguration and structural reconstruction.Overall, this project clarifies the role of inflammation in the pathogenesis of atrial fibrillation, which provides a theoretical and experimental basis for the clinical diagnosis and treatment of atrial fibrillation.

心房颤动是临床最常见的心律失常之一，其发病机制是目前的研究热点。房颤的发生和维持伴随着心房电重构和结构重构，而炎症反应被认为是房颤发病的重要环节。现有国内外学者认为抑癌基因PDCD4作为促炎因子在炎症反应中发挥了重要作用，但其是否通过炎症反应影响了心房重构尚不明确。基于上述研究背景，我们推测PDCD4基因可能与心房重构相关。为证实这个推测，我们拟构建PDCD4过表达转基因及PDCD4基因敲除小鼠模型，选择同种同龄基因正常的小鼠作对照，观察三组小鼠血清炎性因子表达情况、心房肌有效不应期的变化及心房肌纤维化水平，从而探究PDCD4高表达或缺失对小鼠机体炎症反应以及心房电重构及结构重构的影响。以期阐明PDCD4基因高表达或缺失导致小鼠体内炎症反应增强或减弱，从而使心房电重构、结构重构发生变化，为阐明炎症在房颤发病中的作用提供理论和实验依据，为房颤的临床诊疗提供新思路。

心房颤动是临床最常见的心律失常之一，并且被认为是导致心血管病患者死亡的独立危险因素之一。房颤的发生和维持伴随着心房电重构和结构重构，而炎症反应被认为是房颤发病的重要环节。基于PDCD4基因与炎症反应之间的关系，我们推测PDCD4基因可能与心房重构相关。我们通过构建PDCD4过表达转基因及PDCD4基因敲除小鼠模型，选择同种同龄基因正常的小鼠作对照进行了一系列研究。我们发现PDCD4在心房结构重构方面发挥作用，引起心房纤维化，并通过上调或者下调Collagen I、Collagen III、Fibronectin、MMp2、α-SMA蛋白的表达，从而促进或者抑制心房结构重构。同时，我们首次发现PDCD4在心房电重构中发挥了重要的调节作用，其可增加小鼠房颤诱发率、缩短AERP、延长房颤持续时间，从而增加房颤易感性；该基因敲除后明显降低房颤诱发率、延长AERP、缩短房颤持续时间，从而降低了房颤易感性，抑制心房电重构。进一步机制研究发现该基因过表达可以促进IL-6、IL-17A、TNF、IFN-γ等炎性细胞因子分泌，抑制IL-2、IL-4等细胞因子，通过调节促炎或者抑炎细胞因子影响小鼠体内的炎症反应，从而导致心房重构的发生发展。最后通过全转录组测序发现PDCD4基因过表达或者敲除能引起心房组织中大量的mRNA、lncRNA以及miRNA的表达上调或者下调，这些差异表达的RNA可能在转录组水平参与了房颤的发生、发展过程。差异表达的基因参与PPAR信号通路、ECM受体相互作用通路等信号通路过程。总之，我们首次阐明PDCD4基因在心房结构重构以及电重构、炎症因子等方面的作用，为PDCD4基因在房颤发病中的作用提供理论和实验依据，为房颤的临床诊疗提供了新思路和见解：在动物体内敲除PDCD4的可以延长AERP、降低房颤易感性，并抑制心房结构重构，这表明抑制PDCD4可能是房颤治疗的一个新的潜在靶点。