Venkatasubramanian, R.; Darrah, M. A.; Mahoney, S. A.; Hutton, D. A.; Maurer, G. S.; Ludwig, K. R.; VanDongen, N. S.; Greenberg, N. T.; Longtine, A. G.; Brunt, V. E.; Singh, P.; Galligan, J. J.; Trujillo, M. N.; Kapahi, P.; Melov, S.; Campisi, J.; Rossman, M. J.; Seals, D. R.; Clayton, Z. S.

Background: Mechanisms underlying Doxorubicin (Doxo) chemotherapy-induced aortic stiffening are incompletely understood. Objectives: 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. Methods: 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 ex vivo (aortic elastic modulus) and examined the contribution of glycation stress. Results: Doxo increased aortic PWV (425 vs. control, 353 cm/sec; P<0.05), an effect prevented by both GCV (348 cm/sec) and ABT263 (342 cm/sec; P<0.05 for both vs. Doxo). Plasma from Doxo-treated mice induced aortic stiffening ex vivo (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. Conclusion: Cellular senescence and the circulating SASP milieu contribute to Doxo-induced aortic stiffening. Senolytics hold promise for preserving aortic stiffening following Doxo exposure.