氧化应激及细胞内钙信号通路在糖尿病心房重构中的作用及抗氧化剂的干预研究

The potential mechaism between diabetes and atrial fibrillation (AF) is unclear. Our previous work suggests that inflammation and oxidative stress play an important role in the atrial remodeling in diabetes. Recent studies demonstrated intracellular calcium signal pathway promotes the development of AF, oxidative stress may regulate calcium signal pathway to cause atrial remodeling in diabetes. Our study hopthesizes that oxidative stress regulate the function of the key proteins in the calcium signal pathway including L-type calcium channel, Ryanodine receptor2 and Ca2+ ATPase Serca2a to promote diabetic atrial remodeling. Based on our previous work, our present study investigated the atrial electrical and structral remodeing in alloxan-induced diabetic rabbits, expression and activity of NADPH oxidase, atrial L-type channel currents and intracellular calcium concentration changes and calcium regulatory proteins expression changes, and its potential relationship between atrial remodeling and AF induction. We also evaluate preventive effects from antioxidants including apocynin, allopurinol and probucol. From different aspects, our study try to clarify the potential role of oxidative stress and intracellular calcium signal pathway in atrial remodeling and AF development in diabetes and preventive effects of antioxidants, and will provide novel therapeutic target for prevention and treatment of AF.

糖尿病导致心房颤动（房颤）发生的机制尚不清楚，我们前期工作提示炎症和氧化应激在糖尿病所致心房重构中发挥重要作用。近来研究提示细胞内钙信号通路参与房颤发生，氧化应激可能通过调节钙信号通路参与糖尿病心房重构。本课题设想氧化应激通过对细胞内L-型钙通道，RyR2受体、SERCA2a等钙信号通路关键蛋白的调控促进糖尿病心房重构的发生。在前期研究基础上，通过建立四氧嘧啶介导的兔糖尿病模型，从整体、细胞、离子通道及分子生物学水平评价糖尿病兔心房电重构和结构性重构，心房肌NAPDH氧化酶表达及活性变化，观察心房肌细胞膜钙离子流，细胞内钙离子浓度变化，以及多种钙调控蛋白表达变化，及其与心房重构和房颤诱发的关系，同时评价Apocynin、别嘌呤醇及普罗布考等抗氧化剂的干预作用。从多个层次阐明氧化应激及细胞内钙信号通路在糖尿病心房重构和房颤发生的作用及抗氧化剂的干预效果，为房颤的防治提供新的思路和靶点。

糖尿病导致心房颤动（房颤）发生的机制尚不清楚，我们前期工作提示炎症和氧化应激在糖尿病所致心房重构中发挥重要作用。在前期研究基础上，通过建立四氧嘧啶介导的兔糖尿病模型，从整体、细胞、离子通道及分子生物学水平评价糖尿病兔心房电重构和结构性重构，心房肌 NAPDH 氧化酶表达及活性变化，观察心房肌细胞膜钙离子流，细胞内钙离子浓度变化，以及多种钙调控蛋白表达变化及其与心房重构和房颤诱发的关系，同时评价Apocynin、别嘌呤醇及普罗布考等抗氧化剂的干预作用。研究结果显示抗氧化剂Apocynin、别嘌呤醇和普罗布考可以逆转糖尿病导致的心房电重构和结构重构、下调糖尿病导致心房TGF-β, NF-κB, P-p38, P-JNK, ERK and P-ERK蛋白表达增加，预防房颤发生。别嘌呤醇对糖尿病导致的心房肌细胞的钙调控蛋白表达和L-型钙电流异常有改善作用。此外，我们首次证明普罗布考可以降低阵发房颤患者左房直径，缩短P波离散度，减少房颤发作次数，以上有益作用可能与普罗布考对心房重构的改善作用有关。本项目从多个层次阐明氧化应激及细胞内钙信号通路在糖尿病心房重构和房颤发生的作用及抗氧化剂的干预效果，为房颤的防治提供新的思路和靶点。