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Mapping genetic modifiers of radiation-induced cardiotoxicity to rat chromosome 3. Am J Physiol Heart Circ Physiol 2019 06 01;316(6):H1267-H1280

Date

03/09/2019

Pubmed ID

30848680

Pubmed Central ID

PMC6620678

DOI

10.1152/ajpheart.00482.2018

Scopus ID

2-s2.0-85066837925   5 Citations

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-3BN consomic) significantly attenuated radiation-induced cardiotoxicity. SS-3BN rats had less radiation-induced cardiotoxicity than SS rats, as measured by survival, pleural and pericardial effusions, echocardiogram parameters, and histological damage. Mast cells, previously shown to have predominantly protective roles in radiation-induced cardiotoxicity, were increased in the more resistant SS-3BN hearts postradiation. RNA sequencing from SS and SS-3BN hearts at 1 wk postradiation 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 vs. SS-3BN consomic hearts postradiation. Collectively, these data confirm the existence of heritable modifiers in radiation-induced cardiotoxicity and provide multiple biomarkers, pathways, and candidate genes for future analyses. NEW & NOTEWORTHY This novel study reveals that heritable genetic factors have the potential to modify normal tissue sensitivity to radiation. Gene variant(s) on rat chromosome 3 can contribute to enhanced cardiotoxicity displayed in the SS rats vs. the BN and SS-3BN consomic rats. Identifying genes that lead to understanding the mechanisms of radiation-induced cardiotoxicity represents a novel method to personalize radiation treatment, as well as predict the development of radiation-induced cardiotoxicity.

Author List

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

Authors

Meetha M. Medhora PhD Professor in the Radiation Oncology department at Medical College of Wisconsin
Paula E. North MD, PhD Professor in the Pathology department at Medical College of Wisconsin
Hallgeir Rui MD, PhD Vice Chair, Professor in the Pathology department at Medical College of Wisconsin
Yunguang Sun MD, PhD Assistant Professor in the Pathology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Chromosome Mapping
Chromosomes, Mammalian
Disease Models, Animal
Female
Gene Expression Regulation
Genes, Modifier
Genetic Variation
Heart Diseases
Male
Mast Cells
Myocardium
NF-E2-Related Factor 2
Oxidative Stress
Radiation Injuries
Rats, Inbred BN
Rats, Inbred Dahl
Signal Transduction
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