Venkatasubramanian Ravinandan, Darrah Mary A, Mahoney Sophia A, Hutton David A, Maurer Grace S, Ludwig Katelyn R, Van Dongen Nicholas S, Greenberg Nathan T, Longtine Abigail G, Brunt Vienna E, Singh Parminder, Galligan James J, Trujillo Marissa N, Kapahi Pankaj, Melov Simon, Rossman Matthew J, Seals Douglas R, Clayton Zachary S
University of Colorado Boulder (R.V., M.A.D., S.A.M., D.A.H., G.S.M., K.R.L., N.S.V.D., N.T.G., A.G.L., V.E.B., M.J.R., D.R.S., Z.S.C.).
University of Colorado Anschutz Medical Campus, Aurora (V.E.B., Z.S.C.).
Hypertension. 2025 Aug 1. doi: 10.1161/HYPERTENSIONAHA.125.25408.
Mechanisms underlying doxorubicin chemotherapy-induced aortic stiffening are incompletely understood.
To determine the role of cellular senescence and the senescence-associated secretory phenotype (SASP) in mediating doxorubicin-induced aortic stiffening and the influence of senolytic therapy.
Aortic stiffness (aortic pulse wave velocity) and associated mechanisms were assessed in young adult p16-3MR mice, a model that allows for genetic-based clearance of senescent cells with ganciclovir. Young (4-6 months) mice were injected with doxorubicin and subsequently treated with ganciclovir or the senolytic ABT263. We evaluated the influence of SASP-associated circulating factors in plasma (the circulating SASP milieu) in mediating aortic stiffening ex vivo (aortic elastic modulus) and examined the contribution of glycation stress.
Doxorubicin increased aortic pulse wave velocity (425±6 versus control, 353±5 cm/s; <0.0001), an effect prevented by both ganciclovir (348±4 cm/s) and ABT263 (342±7 cm/s; <0.0001 for both versus doxorubicin). Plasma from doxorubicin-treated mice induced aortic stiffening ex vivo (=0.02 versus plasma from control mice), whereas plasma from doxorubicin-ganciclovir and doxorubicin-ABT263 groups did not. Glycation stress was implicated in SASP-mediated aortic stiffening with doxorubicin, as inhibition of receptor-mediated glycation stress signaling attenuated plasma-induced aortic stiffening.
Cellular senescence and the circulating SASP milieu contribute to doxorubicin-induced aortic stiffening. Senolytics hold promise for preserving aortic stiffening following doxorubicin exposure.
阿霉素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）及相关机制，该模型可通过更昔洛韦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，随后用更昔洛韦或衰老细胞溶解剂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）在体外介导主动脉僵硬（主动脉弹性模量）中的作用，并研究了糖基化应激的作用。
阿霉素增加了主动脉脉搏波速度（425±6 vs 对照组353±5 cm/s；<0.0001），更昔洛韦（348±4 cm/s）和ABT263（342±7 cm/s；两者与阿霉素相比均<0.0001）均可预防这种作用。阿霉素处理小鼠的血浆在体外可诱导主动脉僵硬（=0.02 vs 对照小鼠血浆），而阿霉素 - 更昔洛韦组和阿霉素 - 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弱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维持主动脉僵硬。
