Author + information
- Zachary S. Clayton, PhDa@ZachSClayton,
- Vienna E. Brunt, PhDa,
- David A. Hutton, BAa,
- Nicholas S. VanDongen, MSa,
- Angelo D’Alessandro, PhDb,
- Julie A. Reisz, PhDb,
- Brian P. Ziemba, PhDa and
- Douglas R. Seals, PhDa,∗ ()
- aDepartment of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado
- bDepartment of Medicine, Anschutz Medical Campus, University of Colorado Denver, Aurora, Colorado
- ↵∗Address for correspondence:
Dr. Douglas R. Seals, Department of Integrative Physiology, University of Colorado Boulder, 1725 Pleasant Street, 354 UCB, Boulder, Colorado 80309.
Background Doxorubicin (DOXO) chemotherapy increases risk for cardiovascular disease in part by inducing endothelial dysfunction in conduit arteries. However, the mechanisms mediating DOXO-associated endothelial dysfunction in (intact) arteries and treatment strategies are not established.
Objectives We tested the hypothesis that DOXO impairs endothelial function in conduit arteries via excessive mitochondrial reactive oxygen species (ROS) and that these effects could be prevented by treatment with a mitochondrial-targeted antioxidant (MitoQ).
Methods Endothelial function (endothelium-dependent dilation [EDD] to acetylcholine) and vascular mitochondrial ROS were assessed 4 weeks following administration (10 mg/kg intraperitoneal injection) of DOXO. A separate cohort of mice received chronic (4 weeks) oral supplementation with MitoQ (drinking water) for 4 weeks following DOXO.
Results EDD in isolated pressurized carotid arteries was 55% lower 4 weeks following DOXO (peak EDD, DOXO: 42 ± 7% vs. sham: 94 ± 3%; p = 0.006). Vascular mitochondrial ROS was 52% higher and manganese (mitochondrial) superoxide dismutase was 70% lower after DOXO versus sham (p = 0.0008). Endothelial function was rescued by administration of the mitochondrial-targeted antioxidant, MitoQ, to the perfusate. Exposure to plasma from DOXO-treated mice increased mitochondrial ROS in cultured endothelial cells. Analyses of plasma showed differences in oxidative stress-related metabolites and a marked reduction in vascular endothelial growth factor A in DOXO mice, and restoring vascular endothelial growth factor A to sham levels normalized mitochondrial ROS in endothelial cells incubated with plasma from DOXO mice. Oral MitoQ supplementation following DOXO prevented the reduction in EDD (97 ± 1%; p = 0.002 vs. DOXO alone) by ameliorating mitochondrial ROS suppression of EDD.
Conclusions DOXO-induced endothelial dysfunction in conduit arteries is mediated by excessive mitochondrial ROS and ameliorated by mitochondrial-specific antioxidant treatment. Mitochondrial ROS is a viable therapeutic target for mitigating arterial dysfunction with DOXO.
Dr. Clayton was supported by T32 DK007135 & F32 HL151022. Dr. Seals was supported by R01 AG055822. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: CardioOncology author instructions page.
- Received May 14, 2020.
- Revision received June 17, 2020.
- Accepted June 24, 2020.
- 2020 The Authors