Research Center, Montreal Heart Institute, Université de Montréal, 5000 Belanger Street, Montreal, Quebec H1T 1C8, Canada.
Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir-William-Osler, Montreal, Quebec H3G 1Y6, Canada.
Cardiovasc Res. 2024 Apr 30;120(5):506-518. doi: 10.1093/cvr/cvae003.
Cellular senescence is a stress-related or aging response believed to contribute to many cardiac conditions; however, its role in atrial fibrillation (AF) is unknown. Age is the single most important determinant of the risk of AF. The present study was designed to (i) evaluate AF susceptibility and senescence marker expression in rat models of aging and myocardial infarction (MI), (ii) study the effect of reducing senescent-cell burden with senolytic therapy on the atrial substrate in MI rats, and (iii) assess senescence markers in human atrial tissue as a function of age and the presence of AF.
AF susceptibility was studied with programmed electrical stimulation. Gene and protein expression was evaluated by immunoblot or immunofluorescence (protein) and digital polymerase chain reaction (PCR) or reverse transcriptase quantitative PCR (messenger RNA). A previously validated senolytic combination, dasatinib and quercetin, (D+Q; or corresponding vehicle) was administered from the time of sham or MI surgery through 28 days later. Experiments were performed blinded to treatment assignment. Burst pacing-induced AF was seen in 100% of aged (18-month old) rats, 87.5% of young MI rats, and 10% of young control (3-month old) rats (P ≤ 0.001 vs. each). Conduction velocity was slower in aged [both left atrium (LA) and right atrium (RA)] and young MI (LA) rats vs. young control rats (P ≤ 0.001 vs. each). Atrial fibrosis was greater in aged (LA and RA) and young MI (LA) vs. young control rats (P < 0.05 for each). Senolytic therapy reduced AF inducibility in MI rats (from 8/9 rats, 89% in MI vehicle, to 0/9 rats, 0% in MI D + Q, P < 0.001) and attenuated LA fibrosis. Double staining suggested that D + Q acts by clearing senescent myofibroblasts and endothelial cells. In human atria, senescence markers were upregulated in older (≥70 years) and long-standing AF patients vs. individuals ≤60 and sinus rhythm controls, respectively.
Our results point to a potentially significant role of cellular senescence in AF pathophysiology. Modulating cell senescence might provide a basis for novel therapeutic approaches to AF.
细胞衰老被认为是一种与压力相关或与衰老有关的反应，它可能导致许多心脏疾病；然而，其在心房颤动（AF）中的作用尚不清楚。年龄是 AF 风险的最重要决定因素。本研究旨在：（i）评估衰老和心肌梗死（MI）大鼠模型中的 AF 易感性和衰老标志物表达；（ii）研究使用 Senolytic 疗法减少衰老细胞负担对 MI 大鼠心房基质的影响；（iii）评估人类心房组织中衰老标志物随年龄和 AF 存在的变化。
通过程控电刺激研究 AF 易感性。通过免疫印迹或免疫荧光（蛋白质）和数字聚合酶链反应（PCR）或逆转录定量 PCR（信使 RNA）评估基因和蛋白质表达。使用先前验证的 Senolytic 组合，达沙替尼和槲皮素（D+Q；或相应的载体），从假手术或 MI 手术开始给药，持续 28 天。实验在不知道治疗分配的情况下进行。在 100%的老年（18 个月）大鼠、87.5%的年轻 MI 大鼠和 10%的年轻对照组（3 个月）大鼠中观察到起搏诱导的 AF（P ≤ 0.001 与每组相比）。在老年（左心房[LA]和右心房[RA]）和年轻 MI（LA）大鼠中，传导速度较慢，与年轻对照组大鼠相比（P ≤ 0.001 与每组相比）。与年轻对照组大鼠相比，老年（LA 和 RA）和年轻 MI（LA）大鼠的心房纤维化更严重（P < 0.05 与每组相比）。 Senolytic 治疗减少了 MI 大鼠的 AF 诱导性（从 MI 载体中的 9/9 只大鼠，89%降至 MI D + Q 中的 0/9 只大鼠，0%，P < 0.001）并减轻了 LA 纤维化。双重染色表明，D + Q 通过清除衰老的肌成纤维细胞和内皮细胞起作用。在人类心房中，衰老标志物在年龄较大（≥70 岁）和长期 AF 患者中上调，与年龄≤60 岁和窦性心律对照组相比分别上调。
我们的结果表明细胞衰老在 AF 病理生理学中可能具有重要作用。调节细胞衰老可能为 AF 的新治疗方法提供基础。
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