Nucleus-mitochondria positive feedback loop formed by ERK5 S496 phosphorylation-mediated poly (ADP-ribose) polymerase activation provokes persistent pro-inflammatory senescent phenotype and accelerates coronary atherosclerosis after chemo-radiation.
Nucleus-mitochondria positive feedback loop formed by ERK5 S496 phosphorylation-mediated poly (ADP-ribose) polymerase activation provokes persistent pro-inflammatory senescent phenotype and accelerates coronary atherosclerosis after chemo-radiation.
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DOI：
10.1016/j.redox.2021.102132
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发表时间：
2021-11
期刊：
影响因子：
11.4
通讯作者：
Abe JI
中科院分区：
文献类型：
--
作者：
Kotla S;Zhang A;Imanishi M;Ko KA;Lin SH;Gi YJ;Moczygemba M;Isgandarova S;Schadler KL;Chung C;Milgrom SA;Banchs J;Yusuf SW;Amaya DN;Guo H;Thomas TN;Shen YH;Deswal A;Herrmann J;Kleinerman ES;Entman ML;Cooke JP;Schifitto G;Maggirwar SB;McBeath E;Gupte AA;Krishnan S;Patel ZS;Yoon Y;Burks JK;Fujiwara K;Brookes PS;Le NT;Hamilton DJ;Abe JI
癌症幸存者的心血管疾病（CVD）发病率高于一般人群。几种癌症治疗被认为是CVD的危险因素，但没有具体的治疗方法。许多癌症治疗激活共享的信号传导事件，其将髓样细胞（MC）重编程为持续衰老相关分泌表型（SASP）并因此发生CVD，但确切的机制仍不清楚。本研究旨在通过研究化学辐射如何诱导持续性SASP来提供机制见解和潜在的治疗方法。我们产生了ERK 5 S496 A基因敲入小鼠，并通过评估其吞噬能力、抗氧化相关分子表达、端粒长度和炎症基因表达来确定骨髓细胞（MCs）中的SASP。候选SASP诱导剂通过使用ERK 5转录活性报告细胞系统的高通量筛选来鉴定。各种化疗药物和电离辐射（IR）上调p90 RSK介导的ERK 5 S496磷酸化。多柔比星和IR引起代谢变化，伴随烟酰胺腺嘌呤二核苷酸耗竭，并通过p90 RSK-ERK 5调节和聚（ADP-核糖）聚合酶（PARP）激活（形成核-线粒体正反馈环）导致线粒体顿抑（可逆性线粒体功能障碍，在ATP耗竭下未显示任何细胞死亡）。这种反馈回路重新编程MC以诱导持续的SASP状态，并最终使MC对活性氧更敏感。这种引发也检测到循环单核细胞从癌症患者后IR。当PARP活性被短暂抑制时，IR，线粒体顿抑，引发，巨噬细胞浸润，冠状动脉粥样硬化被根除。p90 RSK-ERK 5模块通过调节PARP激活在SASP介导的线粒体顿抑中起关键作用。我们的数据首次表明，由p90 RSK-ERK 5 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状态中起着至关重要的作用，并且还提供了临床前证据，支持仅在放射治疗时短暂抑制PARP激活可以预防癌症幸存者未来的CVD。高通量筛选检测作为p90 RSK-ERK 5调节剂的化学辐射，其诱导衰老相关分泌表型（SASP）。化疗-放射引发线粒体（mt）顿抑（可逆的mt功能障碍，在ATP耗竭下不显示任何细胞死亡）。MT顿抑是由p90 RSK-ERK 5调节和PARP激活引起的，其形成核-线粒体正反馈回路。这种反馈回路重新编程骨髓细胞（MC），以诱导持续的SASP状态，并最终使MC对活性氧更敏感。当PARP活性在IR时被短暂抑制时，线粒体致晕、启动、巨噬细胞浸润和冠状动脉粥样硬化都被根除。
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. High-throughput screening detects chemo-radiation as p90RSK-ERK5 modulator, which induces senescence-associated secretory phenotype (SASP). Chemo-radiation instigates mitochondrial (mt) stunning (reversible mt dysfunction without showing any cell death under ATP depletion). Mt stunning is provoked by p90RSK-ERK5 modulation and PARP activation, which forms a nucleus-mitochondria positive feedback loop. This feedback loop reprogramed myeloid cells (MCs) to induce a sustained SASP state, and ultimately prime MCs to be more sensitive to reactive oxygen species. When PARP activity is transiently inhibited at the time of IR, mitochondrial stunning, priming, macrophage infiltration, and coronary atherosclerosis are all eradicated.
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DOI：
10.1146/annurev-pathol-121808-102144
发表时间：
2010
期刊：
Annual review of pathology
影响因子：
--
作者：
Coppé JP;Desprez PY;Krtolica A;Campisi J
通讯作者：
Campisi J
影响因子：
3.5
作者：
Chalmers, Anthony J.;Lakshman, Mina;Bristow, Robert G.
通讯作者：
Bristow, Robert G.
影响因子：
64.8
作者：
Chouchani, Edward T.;Pell, Victoria R.;Gaude, Edoardo;Aksentijevic, Dunja;Sundier, Stephanie Y.;Robb, Ellen L.;Logan, Angela;Nadtochiy, Sergiy M.;Ord, Emily N. J.;Smith, Anthony C.;Eyassu, Filmon;Shirley, Rachel;Hu, Chou-Hui;Dare, Anna J.;James, Andrew M.;Rogatti, Sebastian;Hartley, Richard C.;Eaton, Simon;Costa, Ana S. H.;Brookes, Paul S.;Davidson, Sean M.;Duchen, Michael R.;Saeb-Parsy, Kourosh;Shattock, Michael J.;Robinson, Alan J.;Work, Lorraine M.;Frezza, Christian;Krieg, Thomas;Murphy, Michael P.
通讯作者：
Murphy, Michael P.
影响因子：
45.3
作者：
Chow, Eric J.;Chen, Yan;Yasui, Yutaka
通讯作者：
Yasui, Yutaka
影响因子：
9.8
作者：
Coppé JP;Patil CK;Rodier F;Sun Y;Muñoz DP;Goldstein J;Nelson PS;Desprez PY;Campisi J
通讯作者：
Campisi J