Walaszczyk Anna, Dookun Emily, Redgrave Rachael, Tual-Chalot Simon, Victorelli Stella, Spyridopoulos Ioakim, Owens Andrew, Arthur Helen M, Passos João F, Richardson Gavin D
Cardiovascular Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, UK.
Aging Cell. 2019 Jun;18(3):e12945. doi: 10.1111/acel.12945. Epub 2019 Mar 28.
Cardiovascular disease is the leading cause of death in individuals over 60 years old. Aging is associated with an increased prevalence of coronary artery disease and a poorer prognosis following acute myocardial infarction (MI). With age, senescent cells accumulate in tissues, including the heart, and contribute to age-related pathologies. However, the role of senescence in recovery following MI has not been investigated. In this study, we demonstrate that treatment of aged mice with the senolytic drug, navitoclax, eliminates senescent cardiomyocytes and attenuates profibrotic protein expression in aged mice. Importantly, clearance of senescent cells improved myocardial remodelling and diastolic function as well as overall survival following MI. These data provide proof-of-concept evidence that senescent cells are major contributors to impaired function and increased mortality following MI and that senolytics are a potential new therapeutic avenue for MI.
心血管疾病是60岁以上人群的主要死因。衰老与冠状动脉疾病患病率增加以及急性心肌梗死(MI)后较差的预后相关。随着年龄增长,衰老细胞在包括心脏在内的组织中积累,并导致与年龄相关的病理变化。然而,衰老在心肌梗死后恢复中的作用尚未得到研究。在本研究中,我们证明用衰老细胞溶解药物navitoclax治疗老年小鼠可消除衰老的心肌细胞,并减弱老年小鼠中促纤维化蛋白的表达。重要的是,清除衰老细胞改善了心肌重构和舒张功能以及心肌梗死后的总体生存率。这些数据提供了概念验证证据,表明衰老细胞是心肌梗死后功能受损和死亡率增加的主要原因,并且衰老细胞溶解药物是心肌梗死潜在的新治疗途径。