Ang II和Ang-(1-7)对心房成纤维细胞钙平衡和钙处理相关蛋白的影响和相互作用机制研究

Atrial interstitial fibrosis is one of the basic mechanisms of occurrence and maintenance of atrial fibrillation, atrial fibroblasts are regarded as the direct executor of interstitial fibrosis remodeling, and become a new research hotspot. Ang- (1-7) as an endogenous antagonist of Ang II can improve myocardial remodeling, but its mechanism mediated has not been fully elucidated. Inspired from the different effects of Ang II and Ang-(1-7) on calcium ions, the present study for the first time will focus on dynamic regulation of calcium ion balance by profibrotic proliferative of Ca2+/CaMKIIδ and antifibrotic NO/cGMP/PKGβ1, and will explore theirs roles and mechanisms in fibroblasts proliferation and phenotype transformation. From atrial fibroblasts and animal models of two aspects, this study will focus on the effects of Ang II and Ang-(1-7) on Ca2+/CaMKIIδ and NO/cGMP/PKGβ1, and theirs mechanisms of interaction, and eventually clarify the mechanisms of Ang-(1-7) improving atrial fibrosis and remodeling. With the application and development of clinical drug based on Ang-(1-7), the elucidation of the mechanisms is important for opening new ideas of prophylaxis and treatment and finding new therapeutic targets.

心房肌间质纤维化是心房纤颤发生与维持的基本机制之一，成纤维细胞则是间质纤维化重构的直接执行者，并成为新的研究热点。Ang-(1-7)作为内源性Ang II的拮抗剂具有改善心肌重构的作用，然而其介导的信号转导机制尚未完全阐明。本研究从Ang II和Ang-(1-7)对钙离子的不同作用中受到启发，在国内外首次聚焦促纤维化增殖的Ca2+/CaMKIIδ与抗纤维化的NO/cGMP/PKGβ1对钙离子平衡的动态调节及其在成纤维细胞增殖与表型转化中的作用机制，分别从细胞和动物两个层面，着力探讨Ang II和Ang-(1-7)对Ca2+/CaMKIIδ、NO/cGMP/PKGβ1的影响和相互作用机制，最终阐明Ang-(1-7)改善心房纤维化重构的分子机制。随着基于Ang-(1-7)的临床药物应用与开发，这一机制的阐明对于开启心房纤颤防治的新思路和寻找新的治疗靶点具有重要意义。