心钠肽在房颤发生中的作用研究

Our understanding of the genetic basis of atrial fibrillation （AF） is mostly limited to genes encoding ion channels, until a frame shift mutation in the NPPA gene encoding atrial natriuretic peptide (ANP) were identified in a AF family, which provides support for a non-ion-channel basis of AF. We carried out an association study on rs5063, an SNP in NPPA and detected significant association between rs5063 and lone AF in a Chinese Han population. Searching for new variations in NPPA that may responsible for AF discovered four common variations in UTRs and two novel missense mutation, which resulting substitution of highly conserved amino acids in atrial natriuretic peptide (ANP). This is the first report showing mutations resulting substitutions of conserved amino acids in ANP in lone AF patients, indicating that mutations in this gene are likely to be responsible for AF in this cohort,and NPPA may be an important susceptibility gene for AF. We plan to figure out how ANP works in atrial remodeling by investigating its cGMP signal pathway, observing its effects on immune system and RAAS, searching proteins interacting with its receptor, and testing its function in cardiac cell and AF animal model. All of these will shed light on mechanism of AF.

2008 年非离子通道基因NPPA、NUP155 突变导致家族性房颤的发现，是对房颤机制认识的又一次革命。我们通过病例-对照研究不但确认了NPPA在汉族人群中是孤立性房颤的易感基因，而且发现了多个新突变。前期工作证实这些突变改变了心钠肽（ANP）的部分生理效应。我们拟进一步从分子细胞水平、组织器官水平再到动物整体水平多层次观察；从基因的表达、受体-配体相互作用、cGMP信号通路、电生理效应、免疫效应、与RAAS系统的相互作用等多方面进行分析，特别是应用快起搏慢性房颤动物模型结合ANP突变体，以揭示ANP在心肌结构重塑和心电重塑中的作用。研究结果不但能加深对利钠肽系统的认识，还能为房颤的临床诊疗提供新的切入点，可能使ANP不再仅作为心衰的生物标记，而连同其受体可能成为房颤药物靶点。

2008 年非离子通道基因NPPA、NUP155 突变导致家族性房颤的发现，是对房颤机制认识的又一次革命。我们通过病例-对照研究不但确认了NPPA在汉族人群中是孤立性房颤的易感基因，而且发现了多个新突变。我们针对其中一个突变（人p.I137T，对应大鼠p.I138T）通过分子、细胞、组织和基因敲入动物各个水平的研究。基因敲入大鼠模型证实其对经食道电极房颤诱导的敏感性大幅提高，诱导的可持续性加强，诱导后心脏结构重构更严重，是能够导致房颤发生的致病性突变。该心钠肽突变体损害了其激活主要受体NPRA产生cGMP的能力，引起心肌，心肌成纤维细胞TNF信号通路的改变，促进了炎症和细胞增殖，从而促进了心脏结构重构。本研究揭示了ANP在心肌结构重塑和心电重塑中的作用和导致房颤的致病机理，研究结果不但能加深对利钠肽系统的认识，还提示ANP不再仅作为心衰的生物标记，其受体对心房、心室正常功能的保护作用远超以往的认识。