SIRT1对左心房纤维化和房颤易感性的影响

Atrial fibrosis is an irreversible atrial histopathological change and the pathological basis of persistent atrial fibrillation and rigid left atrial syndrome. The development of anti-fibrosis drugs has become the focus of current domestic and foreign researches. However, there are only few types of multi-targeted anti-fibrosis drugs, which show poor long-term efficacy on heart diseases.We found that gene silencing regulatory proteins (SIRT1) is one of the core regulatory proteins of fibrosis pathways through integrated analysis on bioinformatics software platform. We also found that the expression level of SIRT1 significantly increased in fibrotic atrial myocardium in preliminary experiments. Therefore, we assume that "SIRT1 may be involved in left atrial myocardial fibrosis, and affects atrial fibrillation vulnerability by regulating left atrial remodeling and myocardial fibrosis".To prove this hypothesis, we will first establish and evaluate left atrial fibrosis model induced by mitral regurgitation in mini-pigs; Secondly, elucidate the possible roles of SIRT1 in the process of left atrial fibrosis using SIRT1 activator and SITR1 inhibitor.Finally, we will try to explore the molecular mechanism of SIRT1 action using atrial fibroblasts in vitro experimental system, so as to find potential targets for prevention and treatment of atrial fibrosis and atrial fibrillation.

心房纤维化（Atrial fibrosis）是一种不可逆性心房组织病理改变，也是持续性房颤、左房僵硬综合征等疾病的病理基础。目前抗纤维化的药物开发已成为诸多研究的焦点，但是现有的多靶点抗纤维化药物较少且对心脏疾患的远期疗效欠佳。本实验室通过生物信息学软件平台对纤维化涉及的通路进行整合分析，发现基因沉默调节蛋白（SIRT1）是其中的核心调控枢纽蛋白。我们预实验也发现在心房纤维化过程中SIRT1表达明显增加。故提出"SIRT1可能参与左房心肌纤维化过程，并通过调控左房重构-心肌纤维化影响房颤易感性"的假说。为证实上述假说，本研究首先建立二尖瓣返流致左房纤维化小型猪模型，然后利用SIRT1的激动剂和抑制剂对其进行调控，阐明SIRT1在左房纤维化过程中可能发挥的作用。然后利用心房成纤维细胞体外实验初步探讨SIRT1作用的分子机制，为左心房纤维化-房颤的防治寻找潜在新靶点。

心房纤维化是房颤的病理基础，但是既往的关于心房纤维化的研究都是单部位取材，忽视了心房纤维化不均一的特性。本项目拟通过研究猪二尖瓣返流时左心房不同位置的纤维化程度和电生理参数及差异性，探索二尖瓣返流时导致的左心房不均一纤维化及所致的不均一电生理改变与房颤易感性之间的关系。通过自制“心脏瓣膜内置切割器”建立小型猪二尖瓣返流模型按照功能分区将左心房分为：左心耳，左房顶，左房后壁，二尖瓣峡部，肺静脉口周，房间隔六个部位进行取材，通过masson染色，评价对不同区域心房组织纤维化程度，通过三维标测对不同区域的电生理参数改变进行评价。通过房颤易感性实验评价房颤易感性。通过免疫荧光染色和蛋白印迹检测sirt1在心房组织的表达。二尖瓣返流模型制作成功率高，与对照组相比，二尖瓣返流组在肺静脉口周、左心房后壁、左心房顶部、房间隔纤维化程度升高，而两组的左心耳、二尖瓣峡部的纤维化程度差异不明显。二尖瓣返流组的心房有效不应期平均值较对照组延长。二尖瓣返流组在肺静脉口周、左心房后壁、左心房顶部、房间隔部位的有效不应期较对照组延长，而在二尖瓣峡部和左心耳的部位两组间有效不应期没有差异。二尖瓣返流组房颤易感性较对照组明显增加。Sirt1与纤维化呈负相关。自制“心脏瓣膜内置切割器”建立小型猪二尖瓣返流模型是一种简单、有效的手术方式，模型出现了结构重构和电重构，并且房颤易感性增加，左心房纤维化程度的不均一性导致了电生理改变的不均一性，可能与房颤易感性相关。Sirt1可以抑制心房纤维化的形成。