Abstract
Abstract 119: Mitochondrial Redox Mechanisms Leading To Sustained Radiation-induced Endothelial Injury
Arteriosclerosis, thrombosis, and vascular biology, Vol.41(Suppl_1)
09/2021
DOI: 10.1161/atvb.41.suppl_1.119
Abstract
Rationale:
Radiation therapy strongly increases the risk of developing atherosclerotic vascular disease, such as coronary and carotid artery disease. Recently, we found that
in vitro
inhibition of the mitochondrial Ca
2+
uniporter (MCU) protects from endothelial barrier breakdown following irradiation.
Objective:
To determine the mechanisms by which irradiation initiates vascular wall injury and test potential mitigators.
Methods and Results:
At 24 and 240 h After head and neck irradiation with 12 Gy x-ray, decreased endothelium-dependent vasodilation was seen in carotid arteries of C57Bl/6 mice. This was prevented by pre-infusion of the mitochondrial superoxide scavenger mitoTEMPO. Altered dilation correlated with increased mitochondrial ROS, loss of NO production and mitochondrial, but not nuclear DNA damage in human coronary endothelial cells
in vitro.
Enhancing mitochondrial in contrast to nuclear base excision repair by overexpression of subcellular targeted 8-Oxoguanine glycosylase blocked mitochondrial ROS and maintained NO production at all time points. Similarly, treatment with pravastatin, knockdown of MCU or its pharmacologic inhibition blocked irradiation-induced mitochondrial DNA damage and excess oxidative stress while maintaining NO production. These findings were recapitulated in vivo in a transgenic model of endothelial MCU knockout and in mice pretreated with pravastatin at 24 and 240 h after irradiation. Irradiation hyperpolarized the mitochondrial membrane potential (αψ
mito
) and increased baseline matrix Ca
2+
levels ([Ca
2+
]
m
) as well as Ca
2+
transients. MCU knockdown decreased αψ
mito
,
[Ca
2+
]
m
and Ca
2+
transients as did mitoTEMPO, whereas pravastatin pretreatment hyperpolarized αψ
mito
despite lowering [Ca
2+
]
m
.
Conclusion:
These findings demonstrate that mitochondrial DNA damage after irradiation drives a feed-forward circuit with ROS production and is sufficient to maintain endothelial dysfunction. Irradiation hyperpolarizes αψ
mito
and blocking this or its sequela, increased [Ca
2+
]
m
, prevents irradiation-induced endothelial injury. These findings also suggest additional mechanisms of statins in mitochondria and MCU as a new approach to mitigate irradiation-induced vascular disease.
Details
- Title: Subtitle
- Abstract 119: Mitochondrial Redox Mechanisms Leading To Sustained Radiation-induced Endothelial Injury
- Creators
- Karima Ait-Aissa - University of IowaOlha Koval - Iowa City, IANathanial R Lindsey - University of IowaKimberly Broadhurst - University of IowaIsabella M Grumbach - Roy J. and Lucille A. Carver College of Medicine
- Resource Type
- Abstract
- Publication Details
- Arteriosclerosis, thrombosis, and vascular biology, Vol.41(Suppl_1)
- DOI
- 10.1161/atvb.41.suppl_1.119
- ISSN
- 1079-5642
- eISSN
- 1524-4636
- Language
- English
- Date published
- 09/2021
- Academic Unit
- Cardiovascular Medicine; Internal Medicine; Radiation Oncology
- Record Identifier
- 9984361719002771
Metrics
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