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Mapping Genetic Modifiers of Radiation-Induced Cardiotoxicity to Rat Chromosome 3. Am J Physiol Heart Circ Physiol 2019 Mar 08 PMID: 30848680

Pubmed ID





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-3consomic) significantly attenuated radiation-induced cardiotoxicity. SS-3rats 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-3hearts post-radiation. RNA sequencing from SS and SS-3hearts 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-3consomic 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.

Author List

Schlaak RA, Frei A, Schottstaedt AM, Tsaih SW, Fish BL, Harmann L, Liu Q, Gasperetti T, Medhora MM, North PE, Strande JL, Sun Y, Rui H, Flister MJ, Bergom C


Hallgeir Rui MD, PhD Vice Chair, Professor in the Pathology department at Medical College of Wisconsin
Jennifer Strande MD, PhD Associate Professor in the Medicine department at Medical College of Wisconsin
Yunguang Sun MD, PhD Assistant Professor in the Pathology department at Medical College of Wisconsin

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