Pun Renju, Haas Aliya L, Thapa Aradhana, Takafuji Sylar R, Suzuki Rexton M, Kay Gabrielle F, Zheng Li, Waknitz Michelle, Kim Michael H, Baker Darren J, van Deursen Jan M, Sorgen Paul L, Gundry Rebekah L, North Brian J
Department of Biomedical Sciences, School of Medicine, Creighton University, Omaha, Nebraska, USA.
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Aging Cell. 2025 Sep;24(9):e70160. doi: 10.1111/acel.70160. Epub 2025 Jul 3.
Aging is a prominent risk factor for heart disease, driving pathological cardiac changes such as hypertrophy, fibrosis, and cellular senescence. While BubR1 has been linked to systemic aging in mammalian models, its specific role in regulating cardiac aging remains unclear. Here, we investigated how BubR1 regulates heart aging and its potential contribution to the pathogenesis of cardiac disease, including heart failure. BubR1 insufficiency in mice resulted in marked cardiac hypertrophy, increased fibrosis, and elevated markers of cellular senescence. Transcriptomic profiling revealed widespread disruption in key pathways involved in cardiac function, including ion channel regulation, cytoskeletal organization, and contractile fiber dynamics. Comparative analysis with aged hearts demonstrated shared dysregulated gene networks, linking BubR1 deficiency to age-related cardiac dysfunction. Additionally, BubR1 hypomorphic hearts mirrored transcriptomic changes observed in end-stage heart failure patients, and BubR1 protein levels were found to decline with age in the heart and were also significantly reduced in rodent models of heart failure and in heart failure patients. BubR1 reduction in cardiomyocytes in vitro led to an increased expression of markers of heart failure, hypertrophy, and cytoskeletal remodeling, underscoring an essential and direct role of BubR1 in maintaining cardiomyocyte health. Overall, our data suggest that BubR1 deficiency is a feature of cardiac aging and disease in humans, and that sustaining BubR1 expression may offer a potential therapeutic strategy to mitigate age-associated cardiac decline and improve heart health in the elderly.
衰老 是心脏病的一个突出风险因素，会引发病理性心脏变化，如肥大、纤维化和细胞衰老。虽然在哺乳动物模型中，BubR1与全身衰老有关，但其在调节心脏衰老中的具体作用仍不清楚。在此，我们研究了BubR1如何调节心脏衰老及其对包括心力衰竭在内的心脏病发病机制的潜在影响。小鼠体内BubR1不足导致明显的心脏肥大、纤维化增加以及细胞衰老标志物升高。转录组分析揭示了参与心脏功能的关键通路中存在广泛紊乱，包括离子通道调节、细胞骨架组织和收缩纤维动力学。与老年心脏的比较分析表明存在共同的失调基因网络，将BubR1缺乏与年龄相关的心脏功能障碍联系起来。此外，BubR1低表达的心脏反映了终末期心力衰竭患者中观察到的转录组变化，并且发现BubR1蛋白水平在心脏中随年龄下降，在心力衰竭的啮齿动物模型和心力衰竭患者中也显著降低。体外心肌细胞中BubR1的减少导致心力衰竭、肥大和细胞骨架重塑标志物的表达增加，突出了BubR1在维持心肌细胞健康方面的重要直接作用。总体而言，我们的数据表明，BubR1缺乏是人类心脏衰老和疾病的一个特征，维持BubR1表达可能提供一种潜在的治疗策略，以减轻与年龄相关的心脏衰退并改善老年人的心脏健康。
