Department of Cardiology the First Affiliated Hospital of Harbin Medical University (X.J., Y. Zhang, Y. Zhou, Y. Li).
NHC Key Laboratory of Cell Transplantation, the First Affiliated Hospital of Harbin Medical University (Y. Luo, X.H., Y.G.).
Circ Arrhythm Electrophysiol. 2024 Jul;17(7):e012452. doi: 10.1161/CIRCEP.123.012452. Epub 2024 Jun 19.
Aging is one of the most potent risk determinants for the onset of atrial fibrillation (AF). Sirts (sirtuins) have been implicated in the pathogenesis of cardiovascular disease, and their expression declines with aging. However, whether Sirts involved in age-related AF and its underlying mechanisms remain unknown. The present study aims to explore the role of Sirts in age-related AF and delineate the underlying molecular mechanisms.
Sirt1 levels in the atria of both elderly individuals and aging rats were evaluated using quantitative real-time polymerase chain reaction and Western blot analysis. Mice were engineered to specifically knockout Sirt1 in the atria and right ventricle (Sirt1). Various techniques, such as echocardiography, atrial electrophysiology, and protein acetylation modification omics were employed. Additionally, coimmunoprecipitation was utilized to substantiate the interaction between Sirt1 and RIPK1 (receptor-interacting protein kinase 1).
We discerned that among the diverse subtypes of sirtuin proteins, only Sirt1 expression was significantly diminished in the atria of elderly people and aged rats. The Sirt1 mice exhibited an enlarged atrial diameter and heightened vulnerability to AF. Acetylated proteomics and cell experiments identified that Sirt1 deficiency activated atrial necroptosis through increasing RIPK1 acetylation and subsequent pseudokinase MLKL (mixed lineage kinase domain-like protein) phosphorylation. Consistently, necroptotic inhibitor necrosulfonamide mitigated atrial necroptosis and diminished both the atrial diameter and AF susceptibility of Sirt1 mice. Resveratrol prevented age-related AF in rats by activating atrial Sirt1 and inhibiting necroptosis.
Our findings first demonstrated that Sirt1 exerts significant efficacy in countering age-related AF by impeding atrial necroptosis through regulation of RIPK1 acetylation, highlighting that the activation of Sirt1 or the inhibition of necroptosis could potentially serve as a therapeutic strategy for age-related AF.
衰老时发生心房颤动（房颤）的最强风险因素之一。Sirtuins（沉默信息调节因子 2 相关酶）被认为与心血管疾病的发病机制有关，其表达随年龄增长而下降。然而，Sirtuins 是否参与与年龄相关的房颤及其潜在机制尚不清楚。本研究旨在探讨 Sirtuins 在与年龄相关的房颤中的作用，并阐明其潜在的分子机制。
采用实时定量聚合酶链反应和 Western blot 分析评估老年个体和衰老大鼠心房中的 Sirt1 水平。通过基因工程特异性敲除心房和右心室中的 Sirt1（Sirt1）来构建小鼠模型。采用超声心动图、心房电生理和蛋白质乙酰化修饰组学等多种技术，以及免疫共沉淀来证实 Sirt1 和 RIPK1（受体相互作用蛋白激酶 1）之间的相互作用。
我们发现，在不同的 Sirtuin 蛋白亚型中，只有 Sirt1 在老年个体和衰老大鼠的心房中表达明显降低。Sirt1 敲除小鼠表现出心房直径增大和易发生房颤的倾向。乙酰化蛋白质组学和细胞实验表明，Sirt1 缺失通过增加 RIPK1 乙酰化和随后的伪激酶 MLKL（混合谱系激酶结构域样蛋白）磷酸化来激活心房坏死性凋亡。一致地，坏死性凋亡抑制剂 Necrostatin-1 减轻了 Sirt1 敲除小鼠的心房坏死性凋亡，并减小了心房直径和房颤易感性。白藜芦醇通过激活心房 Sirt1 并抑制坏死性凋亡来预防大鼠与年龄相关的房颤。
我们的研究结果首次表明，Sirt1 通过调节 RIPK1 乙酰化来抑制心房坏死性凋亡，从而在对抗与年龄相关的房颤方面具有显著疗效，提示激活 Sirt1 或抑制坏死性凋亡可能成为与年龄相关的房颤的治疗策略。
