Cellular senescence mediates doxorubicin chemotherapy-induced aortic stiffening via circulating factors
Authors: Darrah Mary , Venkatasubramanian Ravinandan , Mahoney Sophia , Ludwig Katelyn , Hutton David , Brunt Vienna , Rossman Matthew , Campisi Judith , Seals Douglas , Clayton Zachary 
Published: May 2023

Introduction: The common chemotherapeutic agent doxorubicin (DOXO) mediates large elastic artery (aorta) stiffness in part via chronic low-grade inflammation. Cellular senescence is an established source of inflammation, largely as a result of the senescence associated secretory phenotype (SASP). Senescent cells directly contribute to aortic stiffening after DOXO administration, but the mechanistic role of the SASP in mediating DOXO-induced aortic stiffening is unknown. Purpose. To determine if aortic stiffening with DOXO is induced by changes in SASP-associated circulating factors in plasma. Methods: Young adult (6 mo) male p16-3MR mice, a model that allows for genetic clearance of cellular senescence with ganciclovir (GCV), received an intraperitoneal (IP) injection of sham (saline) or DOXO (10 mg/kg in sham). One week later, animals were treated with Vehicle (V; saline) or GCV (25 mg/kg/day in the V) via IP injection for 5 days, which resulted in 4 groups (Sham-V; Sham-GCV; DOXO-V; DOXO-GCV). Aortic stiffness was assessed in vivo via aortic pulse wave velocity (PWV) before Sham/DOXO and after V/GCV administration. Next, aorta rings from young adult (6 mo p16-3MR) male intervention naïve mice were incubated (for 48h) in standard culture media, plus the following conditions: 1) 10% fetal calf serum (FCS, control); 2) 10% Sham-V plasma; 3) 10% DOXO-V plasma; and 4) 10% DOXO-GCV plasma (n=5-7/group). Following the incubation period, aortic intrinsic mechanical wall stiffness was assessed via elastic modulus (an established ex vivo assay of aortic stiffness). Results: Aortic PWV. There was no difference in aortic PWV (cm/sec; Mean ± SEM) between the Sham-treated groups following administration of V or GCV (Sham-V, 352 ± 6; Sham-GCV, 365 ± 3; P=0.60). Mice administered with DOXO-V had higher aortic PWV (424 ± 12; P<0.0001 vs. all groups); whereas aortic PWV in the DOXO-GCV group was similar to the Sham-treated animals (345 ± 5; P=0.88 and 0.28 vs. Sham-V and Sham-GCV, respectively). Circulating SASP-induced changes in aortic elastic modulus. Plasma from the DOXO-V mice increased elastic modulus (kPa) in aorta rings from young intervention-naïve animals ~2-fold (DOXO-V, 10767 ± 765 vs FCS, 5168 ± 1199; P=0.003). Plasma from the Sham-V and DOXO-GCV mice did not influence aortic elastic modulus (Sham-V, 6426 ± 1225; DOXO-GCV, 5268 ± 517; P=0.79 and P=0.99 vs. FCS, respectively). Relation between plasma-induced changes in aortic elastic modulus and aortic PWV. Plasma-induced changes in aortic elastic modulus were significantly correlated (P=0.02; R2=0.29) with aortic PWV following V/GCV administration. Conclusion: The SASP directly contributes to the cellular senescence-associated increase in aortic stiffness after DOXO treatment. NIH K99 HL159241 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.