Senolytic administration following doxorubicin chemotherapy prevents large elastic artery stiffening and endothelial dysfunction
Authors: Venkatasubramanian Ravinandan , Mahoney Sophia , Maurer Grace , Darrah Mary , Ludwig Katelyn , VanDongen Nicholas , Rossman Matthew , Brunt Vienna , Campisi Judith , Seals Douglas , Clayton Zachary 
Published: May 2023

Doxorubicin (DOXO) chemotherapy induces vascular dysfunction (aortic stiffening and endothelial dysfunction). Cellular senescence and the related increase in oxidative stress, notably mitochondrial reactive oxygen species (mtROS), are implicated in DOXO-induced vascular dysfunction. Hypothesis. Targeting cellular senescence, via administration of a senolytic (senescent cell clearing drug), following exposure to DOXO chemotherapy will prevent aortic stiffening and endothelial dysfunction by suppressing excess mtROS bioactivity and preserving nitric oxide (NO) bioavailability. Methods/Results Animals. Young (6 mo) male and female C57BL/6 mice received a single intraperitoneal injection of Sham (saline) or DOXO (10 mg/kg in Sham). One week later, mice received the vehicle (V; 10% EtOH, 30% PEG400, 60% Phosal 50 PG) or the senolytic ABT263 (ABT; 50 mg/kg/day in V) by oral gavage (1 week on; 2 weeks off; 1 week on). There were 4 groups/sex (Sham-V; Sham-ABT; DOXO-V; DOXO-ABT; n=10-12/group). There were no sex differences, so results were combined. Data are mean±SEM. Aortic Stiffness. Aortic stiffness (aortic pulse wave velocity [aPWV, cm/sec]) was assessed pre and post intervention. There were no group differences at baseline ( P=.63). After the dosing period, aPWV increased by 15% in the DOXO-V group (pre: 353±2 vs post: 414±6, P<.05) whereas no differences were observed in the Sham-V, Sham-ABT or DOXO-ABT groups (DOXO-V vs all groups, P<.05). Endothelial Function. DOXO-V animals had impaired endothelial function ( ex vivo carotid artery endothelium dependent dilation [EDD] to acetylcholine) relative to the Sham-V and Sham-ABT groups, and ABT prevented the DOXO-induced reduction in peak EDD (Peak EDD [%]: Sham-V, 92±1; Sham-ABT, 90±2; DOXO-V, 75±4; DOXO-ABT, 95±1; P<.05). To determine the influence of NO in mediating differences in EDD, we assessed EDD in the presence of the NO-synthase inhibitor L-NAME. With L-NAME group differences were abolished. Oxidative Stress. We assessed if ABT prevented the increase in aortic oxidative stress following DOXO by quantifying (immunofluorescence) nitrotyrosine (NT; marker of oxidative stress). Aortic NT was 21% higher with DOXO-V vs Sham-V (877±29 vs 726±73 Arbitrary Units [AU]; P<.05); ABT administration after DOXO prevented the increase in NT (799±19 AU, P<.05 vs DOXO-V). We then interrogated the specific role of mtROS in mediating differences in oxidative stress with ABT. MtROS. DOXO-V mice had 38% higher mtROS (EPR spectroscopy) vs Sham-V (12.8±1.3 vs 9.2±1.1 AU, P<.05). The DOXO-induced increase in mtROS was mitigated by ABT (9.1±1.1 AU; P<.05 vs DOXO-V). Incubation of carotid arteries with MitoQ (mtROS scavenger) restored peak EDD in the DOXO-V group but had no effect on other groups. Conclusion. Senolytic administration following DOXO chemotherapy may be a strategy to prevent aortic stiffening and NO-mediated endothelial dysfunction by preventing the increase in oxidative stress, particularly excess mtROS.

NIH K99 HL159241 and NIH R21 AG078408

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.