房颤重构中Tolv/dox对PI3K/AKt和MAPK信号通路及miRs靶基因的影响

Atrial fibrillation (AF) is one of the most common arrhythmias. The electrical and structural remodeling play an critical effect in the recurrence and maintenace of AF. Our and related studies have showed that the upsteam inhibition of the rennin-angiotensin system (RAS) may be favored as new therapeutic strategy. Angiotensin-converting enzyme inhibitor (ACEI), angiotensin II receptor blocker (ARB), angiotensin-(1-7) and direct renin inhibitor aliskiren may inhibit atrial ion channels electrical remodeling/ionophorous protein expression, reduce atrial fibrosis. In this study, we attempt to study the effects of Tolvaptan/doxycycline (Tolv/Dox) on atrial fibrotic signaling pathway in intermitant hypoxia rate model of AF. Meanwhile, PI3K/AKt and MAPK signaling pathway，ion channels, miRs and their targeting genes Spry-1/PDCD4 by RAS axis inhibition and Tolv/Dox will also be studied. It is remained unclear that the relations between atrial ionic and fibrotic remodeling, miRs, and signaling pathway (PI3K/Akt,MAPK) targeted by RAS axis inhibition and Tolv/Dox.

心房纤颤(AF)是最常见的心律失常之一，电重构和结构重构是AF复发和维持的重要机制。我们的前期研究表明，由肾素-血管紧张素系统(RAS)的上游抑制、血管紧张素转换酶抑制剂(ACEI)和血管紧张素Ⅱ受体阻滞剂(ARB)、Ang-（1-7）、直接肾素抑制剂阿利吉仑（Aliskiren）具有抑制心房离子通道电重构和基因/蛋白表达，抑制心房纤维化，改善AF心房电重构和结构重构的作用。本研究拟建立大鼠间歇缺氧心房纤维化AF模型，从心房肌离子通道和分子水平研究Tolv/Dox对AF电重构的作用，研究RAS轴抑制和托伐普坦/多西环素（Tolv/Dox）对PI3K/AKt/MAPK信号通路、心房纤维化相关miRs及其靶基因的影响，以探讨其对AF结构重构的作用途径。Tolv/Dox对AF电重构和结构重构中PI3K/AKt/MAPK信号通路和miRs及其靶基因的影响未见国内外报告。

心房纤颤(AF)是最常见的心律失常之一，电重构和结构重构是AF复发和维持的重要机制。本研究建立大鼠间歇缺氧心房纤维化AF模型，给予托伐普坦/多西环素（Tolv/Dox）干预因素，利用整体电生理、膜片钳、分子生物学及病理等技术手段，从心房肌整体、细胞电学改变、离子通道和分子水平研究托伐普坦/多西环素（Tolv/Dox）对离子通道、心房纤维化、离子通道分子变化的影响。结果显示：托伐普坦/多西环素（Tolv/Dox）能够显著改善慢性间歇缺氧所致的心房纤维化，减轻心房结构重构和电重构，降低房颤诱发率；其具体的机制可能是通过干预了miRNA、纤维化信号通路（PI3K/Akt/MAPK/TGFβ/ NF-kB）及离子通道蛋白的表达水平。本研究首次阐明了Tolv 和Dox干预心房重构的具体机制，为探索房颤综合治疗的干预靶点提供了新思路。