The incidence of cardiovascular disease (CVD) is higher in cancer survivors than in the general population. Several cancer treatments are recognized as risk factors for CVD, but specific therapies are unavailable. Many cancer treatments activate shared signaling events, which reprogram myeloid cells (MCs) towards persistent senescence-associated secretory phenotype (SASP) and consequently CVD, but the exact mechanisms remain unclear. This study aimed to provide mechanistic insights and potential treatments by investigating how chemo-radiation can induce persistent SASP. We generated ERK5 S496A knock-in mice and determined SASP in myeloid cells (MCs) by evaluating their efferocytotic ability, antioxidation-related molecule expression, telomere length, and inflammatory gene expression. Candidate SASP inducers were identified by high-throughput screening, using the ERK5 transcriptional activity reporter cell system. Various chemotherapy agents and ionizing radiation (IR) up-regulated p90RSK-mediated ERK5 S496 phosphorylation. Doxorubicin and IR caused metabolic changes with nicotinamide adenine dinucleotide depletion and ensuing mitochondrial stunning (reversible mitochondria dysfunction without showing any cell death under ATP depletion) via p90RSK-ERK5 modulation and poly (ADP-ribose) polymerase (PARP) activation, which formed a nucleus-mitochondria positive feedback loop. This feedback loop reprogramed MCs to induce a sustained SASP state, and ultimately primed MCs to be more sensitive to reactive oxygen species. This priming was also detected in circulating monocytes from cancer patients after IR. When PARP activity was transiently inhibited at the time of IR, mitochondrial stunning, priming, macrophage infiltration, and coronary atherosclerosis were all eradicated. The p90RSK-ERK5 module plays a crucial role in SASP-mediated mitochondrial stunning via regulating PARP activation. Our data show for the first time that the nucleus-mitochondria positive feedback loop formed by p90RSK-ERK5 S496 phosphorylation-mediated PARP activation plays a crucial role of persistent SASP state, and also provide preclinical evidence supporting that transient inhibition of PARP activation only at the time of radiation therapy can prevent future CVD in cancer survivors.

癌症幸存者中心血管疾病（CVD）的发病率高于一般人群。几种癌症治疗方法被认为是 CVD 的危险因素，但尚无特定的治疗方法。许多癌症治疗都会激活共享的信号事件，从而将髓样细胞 (MC) 重新编程为持久性衰老相关分泌表型 (SASP)，从而导致 CVD，但确切的机制仍不清楚。本研究旨在通过研究放化疗如何诱导持续性 SASP 来提供机制见解和潜在的治疗方法。我们生成了 ERK5 S496A 敲入小鼠，并通过评估髓样细胞 (MC) 的胞吞能力、抗氧化相关分子表达、端粒长度和炎症基因表达来确定髓样细胞 (MC) 中的 SASP。使用 ERK5 转录活性报告细胞系统通过高通量筛选鉴定候选 SASP 诱导剂。各种化疗药物和电离辐射 (IR) 上调 p90RSK 介导的 ERK5 S496 磷酸化。阿霉素和IR通过p90RSK-ERK5调节和聚（ADP-核糖）聚合酶（PARP）激活（形成细胞核）引起代谢变化，烟酰胺腺嘌呤二核苷酸耗尽，并随后线粒体击晕（可逆线粒体功能障碍，在ATP耗尽下不显示任何细胞死亡） -线粒体正反馈回路。该反馈回路对 MC 进行重新编程，以诱导持续的 SASP 状态，并最终促使 MC 对活性氧更加敏感。在 IR 后癌症患者的循环单核细胞中也检测到了这种启动作用。当 PARP 活性在 IR 时短暂受到抑制时，线粒体击晕、启动、巨噬细胞浸润和冠状动脉粥样硬化都被根除。p90RSK-ERK5 模块通过调节 PARP 激活，在 SASP 介导的线粒体击晕中发挥着至关重要的作用。我们的数据首次表明，p90RSK-ERK5 S496 磷酸化介导的 PARP 激活形成的核-线粒体正反馈环在持续 SASP 状态中发挥着至关重要的作用，并且还提供了临床前证据支持仅在 SASP 状态下短暂抑制 PARP 激活。放射治疗的时间可以预防癌症幸存者未来发生心血管疾病。