Cellular Senescence Mediates Doxorubicin Chemotherapy-Induced Aortic Stiffening: Role of Glycation Stress.

Abstract

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.