Hypertension (Dallas, Tex. : 1979) · 2025
Cellular Senescence Mediates Doxorubicin Chemotherapy-Induced Aortic Stiffening: Role of Glycation Stress.
СтатьяНазвание и аннотация: Перевод в очереди
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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
Аннотация
BACKGROUND: 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.
METHODS: 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.
RESULTS: Doxorubicin increased aortic pulse wave velocity (425±6 versus control, 353±5 cm/s; P<0.0001), an effect prevented by both ganciclovir (348±4 cm/s) and ABT263 (342±7 cm/s; P<0.0001 for both versus doxorubicin). Plasma from doxorubicin-treated mice induced aortic stiffening ex vivo (P=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.
CONCLUSIONS: Cellular senescence and the circulating SASP milieu contribute to doxorubicin-induced aortic stiffening. Senolytics hold promise for preserving aortic stiffening following doxorubicin exposure.
METHODS: 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.
RESULTS: Doxorubicin increased aortic pulse wave velocity (425±6 versus control, 353±5 cm/s; P<0.0001), an effect prevented by both ganciclovir (348±4 cm/s) and ABT263 (342±7 cm/s; P<0.0001 for both versus doxorubicin). Plasma from doxorubicin-treated mice induced aortic stiffening ex vivo (P=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.
CONCLUSIONS: Cellular senescence and the circulating SASP milieu contribute to doxorubicin-induced aortic stiffening. Senolytics hold promise for preserving aortic stiffening following doxorubicin exposure.