Sesns基因在房颤电和结构重构中保护作用及相关机制研究

It has been known that atrial fibrillation (AF) is closely related to aging in epidemiological investigation, but which factor in aging process contributes to AF development is still unknown. Sestrins (Sesns) are a family of highly conserved stress-responsive proteins, which are greatly noticed for its inhibiting aging-related pathologies recently. We found that the increased expression of Sesns could prevent the enlargement and fibrosis of the left atrium in AF patients.Therefore, Sesns are supposed as a protective factor against atrial structural and electrical remodeling by inhibiting mTOR/p70S6K signals and preventing oxidative stress, and therefore reduce AF incidence and persistence. To validate the hypothesis, we will investigate the followings:①Sesns will protect atrium from electrical and structural remodeling by inhibiting oxidative stress in paced HL-1 atrial cells; ②Sesns will prevent fibroblasts activation by inhibiting mTOR/p70S6K signals in atrial fibroblast cells, so as to decrease atrial fibrosis and structural remodeling; ③In dogs with AF, Sesns transfection will prevent atrial structural and electrical remodeling and reduce AF incidence and persistence, whereas Sesns siRNA will increase these remodeling and promote AF development. This investigation will clarify whether Sesns, which known for its antiaging effects recently, have protective effects in AF process, as well as clarify the possible mechanisms of these protective effects. Thus, we will provide novelty means to prevent and treat AF in the future.

房颤和衰老密切相关，但是不清楚衰老过程中哪个环节导致了房颤发生和发展。Sesns是新发现的抗衰老基因，能拮抗氧化应激并抑制mTOR信号通路。我们前期研究发现，房颤时Sesns高表达可以防止心房扩大和纤维化。因此提出假设："Sesns在房颤中起保护作用，通过抗氧化应激和抑制mTOR/p70S6K通路防止心房电和结构重构，减少房颤发生和持续"。为验证假说，本课题将研究：①在HL-1房颤细胞模型上证实Sesns通过抗氧化应激，防止心房电和结构重构；②在心房成纤维细胞中证实Sesns通过调控mTOR/p70S6K通路，抑制成纤维细胞激活，防止心房纤维化；③在房颤犬模型上证实转染外源Sesns基因能防止心房电和结构重构，减少房颤发生和持续，而Sesns 基因沉默能促进电和结构重构，增加房颤发生。本课题将阐明抗衰老基因Sesns能否在房颤中起保护作用及相关机制，为房颤防治提供新的研究方向和治疗靶点。

心房颤动是临床上最常见的心律失常之一，发生方面突出表现为与衰老有关，其主要机制是心房发生电和结构重构，而氧化应激和纤维化是房颤电和结构重构两个最主要机制，Sesns 是一个抗衰老基因，且具有抗氧化应激及抑制mTOR 通路作用。本课题组通过入选房颤患者及非房颤患者，培养HL-1 房颤细胞模型，建立房颤犬动物模型三方面设计实验，得出以下重要结果：（1）持续性房颤患者较非房颤患者，Sesns 表达上调且氧化应激，纤维化，细胞结构破坏均更严重。（2）在HL-1 房颤细胞模型上，Sesns 表达升高后对HL-1 细胞的氧化应激及细胞存活率均有明显保护作用。（3）过表达Sestrin1 及Sestrin2 对Ang II 诱导的SD 大鼠乳鼠心房成纤维细胞纤维化具有保护作用。（4）在房颤犬模型上，Sestrin2 基因能够拮抗氧化应激，改善心房电和结构重构，减少房颤发生和持续，在房颤中起保护作用。（5）HL-1 细胞系过表达Sestrin2 后，较对照组，其动作电位（APD）显著增大，ICa-L 电流密度无显著变化。（6）Sestrin2 基因在房颤中起保护作用的过程中，其具体机制可能与Cacna2d2 蛋白相关，需进一步设计实验证明。以上发现阐明抗衰老基因Sesns 在房颤中具有抗氧化应激，减轻纤维化，保护房颤的作用，为房颤防治提供新的研究方向和治疗靶点。