Venkatasubramanian Ravinandan, Darrah Mary A, Mahoney Sophia A, Hutton David A, Maurer Grace S, Ludwig Katelyn R, VanDongen Nicholas S, Greenberg Nathan T, Longtine Abigail G, Brunt Vienna E, Singh Parminder, Galligan James J, Trujillo Marissa N, Kapahi Pankaj, Melov Simon, Campisi Judith, Rossman Matthew J, Seals Douglas R, Clayton Zachary S
bioRxiv. 2025 May 16:2025.05.13.653823. doi: 10.1101/2025.05.13.653823.
Mechanisms underlying Doxorubicin (Doxo) chemotherapy-induced aortic stiffening are incompletely understood.
Determine the role of cellular senescence and the senescence-associated secretory phenotype (SASP) in mediating Doxo-induced aortic stiffening and the influence of senolytic therapy.
Aortic stiffness (aortic pulse-wave velocity [PWV]), and associated mechanisms were assessed in young adult p16-3MR mice, a model that allows for genetic-based clearance of senescent cells with ganciclovir [GCV]. Young (4-6 month) mice were injected with Doxo and subsequently treated with GCV or the senolytic ABT263. We evaluated the influence of SASP-associated circulating factors in plasma (the circulating SASP milieu) in mediating aortic stiffening (aortic elastic modulus) and examined the contribution of glycation stress.
Doxo increased aortic PWV (425D±D6 vs. control, 353D±D5Dcm/sec; P<0.05), an effect prevented by both GCV (348D±D4Dcm/sec) and ABT263 (342D±D7Dcm/sec; P<0.05 for both vs. Doxo). Plasma from Doxo-treated mice induced aortic stiffening (P<0.05 vs. plasma from control mice), whereas plasma from Doxo-GCV and Doxo-ABT263 groups did not. Glycation stress was implicated in SASP-mediated aortic stiffening with Doxo, as inhibition of receptor mediated glycation stress signaling attenuated plasma-induced aortic stiffening.
Cellular senescence and the circulating SASP milieu contribute to Doxo-induced aortic stiffening. Senolytics hold promise for preserving aortic stiffening following Doxo exposure.
Chemotherapy-induced cardiovascular toxicity is a concern for cancer survivors. This study identifies cellular senescence and the senescence-associated secretory phenotype (SASP) as underlying mechanisms of doxorubicin chemotherapy-induced aortic stiffening - an antecedent to overt cardiovascular disease (CVD). We also provide complementary lines of evidence that glycation stress mediates the mechanistic link between doxorubicin, cellular senescence, the SASP and aortic stiffening. Lastly, we demonstrate the efficacy of senolytic therapy for targeting cellular senescence, the SASP and glycation stress to prevent doxorubicin-induced aortic stiffening. These results offer a novel and clinically actionable approach to preserving vascular health in cancer survivors and mitigating CVD risk.
阿霉素（Doxo）化疗诱导主动脉僵硬的潜在机制尚未完全明确。
确定细胞衰老和衰老相关分泌表型（SASP）在介导阿霉素诱导的主动脉僵硬中的作用以及衰老细胞溶解疗法的影响。
在年轻成年p16-3MR小鼠中评估主动脉僵硬（主动脉脉搏波速度[PWV]）及相关机制，该小鼠模型可通过更昔洛韦[GCV]对衰老细胞进行基于基因的清除。对年轻（4 - 6个月）小鼠注射阿霉素，随后用GCV或衰老细胞溶解剂ABT263进行治疗。我们评估了血浆中与SASP相关的循环因子（循环SASP环境）在介导主动脉僵硬（主动脉弹性模量）中的作用，并研究了糖基化应激的作用。
阿霉素使主动脉PWV增加（425D±D6与对照组353D±D5Dcm/秒相比；P<0.05），GCV（348D±D4Dcm/秒）和ABT263（342D±D7Dcm/秒；两者与阿霉素相比P<0.05）均可预防这种作用。阿霉素处理小鼠的血浆可诱导主动脉僵硬（与对照小鼠血浆相比P<0.05），而阿霉素 - GCV组和阿霉素 - ABT263组的血浆则无此作用。糖基化应激与阿霉素诱导的SASP介导的主动脉僵硬有关，因为抑制受体介导的糖基化应激信号可减轻血浆诱导的主动脉僵硬。
细胞衰老和循环SASP环境促成了阿霉素诱导的主动脉僵硬。衰老细胞溶解剂有望在阿霉素暴露后预防主动脉僵硬。
化疗诱导的心血管毒性是癌症幸存者关注的问题。本研究确定细胞衰老和衰老相关分泌表型（SASP）是阿霉素化疗诱导主动脉僵硬的潜在机制，而主动脉僵硬是明显心血管疾病（CVD）的先兆。我们还提供了补充证据，表明糖基化应激介导了阿霉素、细胞衰老、SASP与主动脉僵硬之间的机制联系。最后，我们证明了衰老细胞溶解疗法针对细胞衰老、SASP和糖基化应激来预防阿霉素诱导的主动脉僵硬的有效性。这些结果为保护癌症幸存者的血管健康和降低CVD风险提供了一种新的且具有临床可操作性的方法。
