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Am J Physiol Heart Circ Physiol. 2019 Mar 8. doi: 10.1152/ajpheart.00482.2018. [Epub ahead of print]

Mapping Genetic Modifiers of Radiation-Induced Cardiotoxicity to Rat Chromosome 3.

Author information

1
Pharmacology & Toxicology, Medical College of Wisconsin, United States.
2
Radiation Oncology, Medical College of Wisconsin, United States.
3
Department of Medicine, Case Western Reserve University.
4
Medical College of Wisconsin, Human and Molecular Genetics Center.
5
Radiation Oncology, Medical College of Wisconsin.
6
Cardiovascular Medicine, Medical College of Wisconsin.
7
Medical College of Wisconsin, United States.
8
Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226.
9
Department of Pathology, Medical College of Wisconsin.
10
Medicine, Medical College of Wisconsin, United States.
11
Physiology, Medical College of Wisconsin, United States.

Abstract

Radiation therapy is used in ~50% of cancer patients to reduce the risk of recurrence and in some cases improve survival. Despite these benefits, doses can be limited by toxicity in multiple organs, including the heart. The underlying causes and biomarkers of radiation-induced cardiotoxicity are currently unknown, prompting the need for experimental models with inherent differences in sensitivity and resistance to the development of radiation-induced cardiotoxicity. We have identified the parental SS (Dahl salt sensitive/Mcwi) rat strain to be a highly-sensitized model of radiation-induced cardiotoxicity. In comparison, substitution of rat chromosome 3 from the resistant BN (Brown Norway) rat strain onto the SS background (SS-3BNconsomic) significantly attenuated radiation-induced cardiotoxicity. SS-3BNrats had less radiation-induced cardiotoxicity than SS rats, as measured by survival, pleural and pericardial effusions, echocardiogram parameters, and histologic damage. Mast cells, previously shown to have predominantly protective roles in radiation-induced cardiotoxicity, were increased in the more resistant SS-3BNhearts post-radiation. RNA sequencing from SS and SS-3BNhearts at 1 week post-radiation revealed 5,098 differentially expressed candidate genes across the transcriptome and 350 differentially expressed genes on rat chromosome 3, which coincided with enrichment of multiple pathways, including mitochondrial dysfunction, sirtuin signaling, and ubiquitination. Upstream regulators of enriched pathways included the oxidative stress modulating transcription factor, Nrf2, which is located on rat chromosome 3. Nrf2 target genes were also differentially expressed in the SS versus SS-3BNconsomic hearts post-radiation. Collectively, these data confirm the existence of heritable modifiers in radiation-induced cardiotoxicity and provide multiple biomarkers, pathways, and candidate genes for future analyses.

KEYWORDS:

RNA sequencing; cardiotoxicity; consomic; genomics; radiation therapy

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