Banerjee Priyanka, Olmsted-Davis Elizabeth A, Deswal Anita, Nguyen Minh Th, Koutroumpakis Efstratios, Palaskas Nicholas L, Lin Steven H, Kotla Sivareddy, Reyes-Gibby Cielito, Yeung Sai-Ching J, Yusuf Syed Wamique, Yoshimoto Momoko, Kobayashi Michihiro, Yu Bing, Schadler Keri, Herrmann Joerg, Cooke John P, Jain Abhishek, Chini Eduardo, Le Nhat-Tu, Abe Jun-Ichi
Academic Institute, Department of Cardiovascular Sciences, Center for Cardiovascular Sciences, Houston Methodist Research Institute, Weill Cornell Medical College, Houston, TX 77030, USA.
Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
J Cardiovasc Aging. 2022;2. doi: 10.20517/jca.2022.13. Epub 2022 Apr 29.
Numerous studies have revealed the critical role of premature senescence induced by various cancer treatment modalities in the pathogenesis of aging-related diseases. Senescence-associated secretory phenotype (SASP) can be induced by telomere dysfunction. Telomeric DNA damage response induced by some cancer treatments can persist for months, possibly accounting for long-term sequelae of cancer treatments. Telomeric DNA damage-induced mitochondrial dysfunction and increased reactive oxygen species production are hallmarks of premature senescence. Recently, we reported that the nucleus-mitochondria positive feedback loop formed by p90 ribosomal S6 kinase (p90RSK) and phosphorylation of S496 on ERK5 (a unique member of the mitogen-activated protein kinase family that is not only a kinase but also a transcriptional co-activator) were vital signaling events that played crucial roles in linking mitochondrial dysfunction, nuclear telomere dysfunction, persistent SASP induction, and atherosclerosis. In this review, we will discuss the role of NAD depletion in instigating SASP and its downstream signaling and regulatory mechanisms that lead to the premature onset of atherosclerotic cardiovascular diseases in cancer survivors.
众多研究揭示了各种癌症治疗方式诱导的早衰在衰老相关疾病发病机制中的关键作用。衰老相关分泌表型（SASP）可由端粒功能障碍诱导。某些癌症治疗诱导的端粒DNA损伤反应可持续数月，这可能是癌症治疗长期后遗症的原因。端粒DNA损伤诱导的线粒体功能障碍和活性氧产生增加是早衰的标志。最近，我们报道由p90核糖体S6激酶（p90RSK）和ERK5上S496位点的磷酸化（丝裂原活化蛋白激酶家族的独特成员，不仅是一种激酶，也是一种转录共激活因子）形成的细胞核-线粒体正反馈环是重要的信号事件，在连接线粒体功能障碍、核端粒功能障碍、持续性SASP诱导和动脉粥样硬化中起关键作用。在这篇综述中，我们将讨论NAD耗竭在引发SASP及其下游信号传导和调节机制中的作用，这些机制导致癌症幸存者过早发生动脉粥样硬化性心血管疾病。
