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Cellular senescence mediates doxorubicin‐induced arterial dysfunction via activation of mitochondrial oxidative stress and the mammalian target of rapamycin
Author(s) -
Hutton David,
Brunt Vienna,
Mahoney Sophia,
Casso Abigail,
Greenberg Nathan,
VanDongen Nicholas,
Ziemba Brian,
Nguyen Kathy,
Melov Simon,
Campisi Judith,
Seals Douglas,
Clayton Zachary
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.00283
Subject(s) - pulse wave velocity , medicine , endothelial dysfunction , arterial stiffness , oxidative stress , aorta , saline , doxorubicin , endocrinology , pharmacology , chemotherapy , blood pressure
The mechanisms underlying arterial dysfunction (large elastic artery [e.g., aorta] stiffening and vascular endothelial dysfunction) caused by the common chemotherapeutic agent doxorubicin (DOXO) are incompletely understood. Purpose To determine if clearance of senescent cells (senolysis) following DOXO would: 1) prevent aortic stiffening via reduced aortic intrinsic mechanical wall stiffness (elastic modulus [EM]), in part due to inhibition of the mammalian target of rapamycin (mTOR); and 2) prevent endothelial dysfunction by preserving nitric oxide (NO) bioavailability and inhibiting excess mitochondrial reactive oxygen species (mtROS) production. Results Young adult (4 mo) p16‐3MR male (n = 5‐9) and female (n = 3‐5) mice received a single IP injection of DOXO (10 mg/ml in saline) or vehicle (V; saline). One week after DOXO, a p16 + senolytic used in p16‐3MR mice, ganciclovir (GCV; 25 mg/kg/day x 5 days), or vehicle (V; saline x 5 days) were administered IP, resulting in 4 groups/sex (DOXO‐V; DOXO‐GCV; V‐V; V‐GCV) that were studied 3 weeks later. No sex differences were observed, so results were combined. Aortic Stiffness No pre‐treatment differences in aortic stiffness (aortic pulse wave velocity [PWV]) were found. DOXO increased aortic PWV by 17% in DOXO‐V ( P = 0.03), which was prevented by senolysis (DOXO‐GCV, Pre vs Post treatment: P = 0.88). These group differences in aortic PWV were explained by differences in aortic EM, which was higher in DOXO‐V mice vs. all groups ( P = 0.02), suggesting senolysis prevented the increased EM with DOXO. Next, we assessed the mTOR‐mediated contribution to aortic EM by incubating (48h) aortic rings from all groups with the mTOR inhibitor, rapamycin, or sham (DMSO). EM was higher in sham‐incubated DOXO‐V vs. V‐V rings (2579±200 vs. 1900±54 kPa, P = 0.04). Rapamycin lowered aortic EM in the DOXO‐V group (rapamycin vs. sham: 1604±115 vs. 2579±200 kPa, P = 0.02), which eliminated group differences. This suggests senolysis prevents aortic stiffening caused by DOXO via mTOR inhibition. Endothelial function DOXO impaired isolated carotid artery endothelium‐dependent dilation (EDD) to acetylcholine, an established bioassay of endothelial function (DOXO‐V vs V‐V: 62±5 vs 93±2 %, P < 0.0001), which was fully prevented with senolysis (DOXO‐GCV: 95±1%). Addition of the NO‐synthase inhibitor, L‐NAME, abolished group differences, suggesting senolysis following DOXO preserves EDD by maintaining NO bioavailability. Administration of the mt‐targeted antioxidant MitoQ eliminated group differences in EDD, suggesting excess mtROS impaired endothelial function in the DOXO‐V group, which was prevented with senolysis. Conclusion Arterial dysfunction with DOXO is mediated by cellular senescence. mTOR and mtROS may be therapeutic targets to prevent/treat DOXO‐mediated arterial dysfunction.