bioRxiv. 2025 May 16. pii: 2025.05.13.653823. [Epub ahead of print]
Ravinandan Venkatasubramanian,
Mary A Darrah,
Sophia A Mahoney,
David A Hutton,
Grace S Maurer,
Katelyn R Ludwig,
Nicholas S VanDongen,
Nathan T Greenberg,
Abigail G Longtine,
Vienna E Brunt,
Parminder Singh,
James J Galligan,
Marissa N Trujillo,
Pankaj Kapahi,
Simon Melov,
Judith Campisi,
Matthew J Rossman,
Douglas R Seals,
Zachary S Clayton.
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 (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 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.
Translational perspective: 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.