醛固酮/Sirt1/AMPK信号通路调控心房颤动时心房代谢重构的机制

Recent studies demonstrated that atrial metabolic remodeling might be an important basis of occurrence and duration of atrial fibrillation (AF). But the potential mechanism is still not very clear. It is generally believed that aldosterone is an important pathogenic factor of AF, and also a key regulatory factor of myocardial energy metabolism. The expression level of aldosterone was significantly increased in atria during AF. Our previous study showed that the expressions of pSirt1 and pAMPK were significantly decreased in atria of AF patients, and 4-week aldosterone infusion led to atrial metabolic remodeling and the down-regulation of pSirt1 and pAMPK in dogs. Based on the findings above, we hypothesize that AF-induced up-regulation of aldosterone resulted in atrial metabolic remodeling by regulating Sirt1/AMPK signaling pathway, and further contributed to the happen and development of AF. Therefore, we aim to verify: first, aldosterone/Sirt1/AMPK signaling pathway induces atrial metabolic remodeling, leads to atrial electrophysiological and structural remodeling, and contributes to occurrence and sustaining of AF; Second, this study examins the regulatory mechanisms of aldosterone/Sirt1/AMPK signaling pathway in atrial metabolic remodeling of atrial myocytes and fibroblasts during AF; finally, we try to clarify the molecular mechanism of atrial metabolic remodeling, which is mediated by aldosrone/Sirt1/AMPK signaling, in regulating electrical and structural remodeling during AF. The present study may be helpful in elucidating the mechanisms of atrial metabolic remodeling, and provide a novel target for preventing AF.

新近研究发现心房代谢重构是房颤发生和持续的重要基质，但其发生机制尚不清楚。已知房颤时心房肌局部醛固酮表达增加，有证据提示醛固酮是心肌能量代谢的重要调控因子。我们前期研究发现慢性房颤患者心房肌关键代谢调控分子pSirt1和pAMPK蛋白表达显著性下调，输注醛固酮四周可引起犬心房肌能量代谢重构，pSirt1和pAMPK蛋白表达显著下调。本课题组在前期工作基础上提出假设：房颤时心房局部醛固酮表达增加，通过Sirt1/AMPK信号通路引起心房代谢重构，促进房颤发生并持续。为验证该假设，本研究将：①验证房颤时醛固酮/Sirt1/AMPK通路引起心房代谢重构，导致心房电和结构重构，促进房颤发生和持续；②证实该通路对心房肌细胞和成纤维细胞能量代谢重构的确切调控作用；③阐明该通路介导的代谢重构对心房肌电和结构重构影响的分子机制。该假设的验证将有助于阐明房颤心房能量代谢重构的调控机制，为房颤防治提供新靶点。

新近研究报道和我们前期研究证实，房颤时心房肌发生能量代谢重构，但其调控作用及相关的机制尚不清楚。本项目拟通过体内、体外水平证实，醛固酮刺激模型和房颤时心房肌代谢发生代谢重构，并且证实醛固酮诱导心房肌代谢重构或异常，进而出现房颤发生。在醛固酮刺激模型研究证实，醛固酮诱导心房肌细胞Sirt1/AMPK信号途径下调，但醛固酮受体拮抗剂可以逆转这些改变。在房颤体内和体外模型证实，房颤时心房肌细胞Sirt1/AMPK信号通路下调，导致心房肌代谢重构，促进房颤发生和持续，但应用醛固酮受体拮抗剂可以抑制其下调进而改善代谢重构。本研究证实，给予醛固酮受体拮抗剂能够抑制房颤时代谢重构，今后为房颤的代谢重构防治提供新的靶点和理论依据。开拓醛固酮受体拮抗剂新的药理作用。临床意义在于，发现醛固酮水平增加患者应早期干预，防治房颤发生。