前列腺素I2及其受体IP在心房纤维化形成中的作用及机制研究

Atrial fibrillation (AF) is one of the most common arrhythmias, and atrial fibrosis plays a key role in the occurrence and maintenance of AF. Our previous studies found that prostaglandin I2 (PGI2) was decreased in the plasma of AF patients compared to healthy people via metabonomics methodology, indicating that PGI2 may be involved in the development of AF. However, the underlying mechanisms are still unclear and need further investigation. Based on our preliminary data, we hypothesize that in the status of atrial fibrosis, PGI2 synthesized and released from atrial fibroblasts (FBs) will decline, along with IP receptors. Decreased interaction of PGI2 and IP will lose control of Ras/MEK/ERK and TGFβ-1/Smad pathway, leading to increase of FBs proliferation and collagen production, and that ends up triggering atrial fibrosis. We will use primary atrial FBs and Angiotensin II-induced atrial fibrosis model to elucidate the function of PGI2-IP in proliferation and secretion of FBs and relative molecular mechanisms, and also explore the effect of PGI2 in atrial remodeling. This study may extend our knowledge of the mechanisms of FBs dysfunction and potentially contribute to the development of novel therapeutic approaches to AF.

心房颤动（AF）是最常见的心律失常之一，心房纤维化是房颤发生和维持的基础。我们前期研究应用超高压液相色谱串联质谱分析发现，PGI2在AF患者血浆中显著降低，提示其可能参与AF的发生和发展。申请者结合前期工作及预实验结果提出假说：在心房纤维化过程中，由于成纤维细胞（FBs）合成PGI2合酶（PTGIS）能力下降，使得PGI2生成减少，同时其受体IP表达降低，二者相互作用减弱，失去了对Ras/MEK/ERK及TGFβ-1/Smad途径的抑制作用，从而促使FBs发生增殖和合成I型、III型胶原增加，导致了心房纤维化的发展。本项目拟选用原代乳鼠心房成纤维细胞和血管紧张素II（AngII）致小鼠心房纤维化模型，给予PGI2干预，从体外和体内两个方面研究PGI2对心房成纤维细胞增殖、合成胶原功能的作用及调控机制，以及对心房结构重构的影响。旨在发现调节心房成纤维细胞功能的新机制，为房颤的治疗提供新靶点。

心房颤动（AF）是最常见的心律失常之一，心房纤维化是房颤发生和维持的基础。目前尚缺乏对心房纤维化有效的干预手段。本项目旨在明确前列腺素I2（PGI2）对心房纤维化的作用及探讨其可能的机制。项目选用血管紧张素II（AngII）胶囊泵持续泵入法成功构建小鼠心房纤维化模型，给予外源性的PGI2 类似物伊洛前列素干预后发现其可以减少小鼠心房纤维化的程度，缩小左心房的大小，改善心房传导紊乱。通过分离培养小鼠心房成纤维细胞，给予PGI2 类似物伊洛前列素干预，发现PGI2可以抑制AngII诱导的成纤维细胞向肌成纤维细胞的转分化以及降低其合成胶原蛋白 I、α-SMA和炎性因子IL-6的功能。在机制探讨上，我们发现补充PGI2可以增加cAMP的含量和PKA的活性，随后通过给予PKA抑制剂 Rp-8Br-cAMPS，发现PGI2抑制AngII诱导的ERK1/2, P38、 NF-kB、IL-6是通过PKA信号通路发挥作用。.项目组利用心脏成纤维细胞特异性启动子Periostin介导的腺相关病毒9（AAV9）构建了特异性敲减小鼠心脏成纤维细胞中的IP受体的模型，并于皮下植入含有Ang II溶液的微囊泵，发现与野生型小鼠相比，IP敲除小鼠心房纤维化程度加重，左房内径增大，房颤发生率升高，房颤持续时间延长。敲减心房成纤维细胞中IP受体可以促进Ang II介导的表型转换、收缩和迁移功能；激活ERK1/2、P38、NF-kB，从而促进IL-6合成；提示PGI2受体IP受体激活可以抑制心房纤维化形成。本项目初步明确了PGI2及其受体IP对心房纤维化的作用及可能机制，为房颤的治疗提供了的新思路。