Differences in Expression of Mitochondrial Complexes Due to Genetic Variants May Alter Sensitivity to Radiation-Induced Cardiac Dysfunction

Abstract

Radiation therapy is received by over half of all cancer patients. However, radiation doses may be constricted due to normal tissue side effects. In thoracic cancers, including breast and lung cancers, cardiac radiation is a major concern in treatment planning. There are currently no biomarkers of radiation-induced cardiotoxicity. Complex genetic modifiers can contribute to the risk of radiation-induced cardiotoxicities, yet these modifiers are largely unknown and poorly understood. We have previously reported the SS (Dahl salt-sensitive/Mcwi) rat strain is a highly sensitized model of radiation-induced cardiotoxicity compared to the more resistant Brown Norway (BN) rat strain. When rat chromosome 3 from the resistant BN rat strain is substituted into the SS background (SS.BN3 consomic), it significantly attenuates radiation-induced cardiotoxicity, demonstrating inherited genetic variants on rat chromosome 3 modify radiation sensitivity. Genes involved with mitochondrial function were differentially expressed in the hearts of SS and SS.BN3 rats 1 week after radiation. Here we further assessed differences in mitochondria-related genes between the sensitive SS and resistant SS.BN3 rats. We found mitochondrial-related gene expression differed in untreated hearts, while no differences in mitochondrial morphology were seen 1 week after localized heart radiation. At 12 weeks after localized cardiac radiation, differences in mitochondrial complex protein expression in the left ventricles were seen between the SS and SS.BN3 rats. These studies suggest that differences in mitochondrial gene expression caused by inherited genetic variants may contribute to differences in sensitivity to cardiac radiation.

Radiation‑induced dysfunction of energy metabolism in the heart results in the fibrosis of cardiac tissues

“…The simple ganoderma lucidum spore oil system these authors developed targeted the myocardial mitochondria and slowed down the production of roS, thus exhibiting a preventative and therapeutic effect on riHd. additionally, the differences in expression levels of mitochondrial genes caused by genetic variants may lead to differences in sensitivity to ionizing radiation (68). collectively, the aforementioned studies revealed that mitochondrial damage was an important target in riHd, and drugs or drug-loaded materials for the repair of mitochondrial damage can reduce radiation-induced heart injury.…”

Lisinopril Mitigates Radiation-Induced Mitochondrial Defects in Rat Heart and Blood Cells

“…A number of different dose and fractionation regimens have been utilized in preclinical studies of RIHD, ranging from large single fractions to more clinically relevant fractionated regimens ( 2 ). We used a fractionated regimen consisting of 8 Gy x 5 fractions, similar to prior studies that have utilized fractionated radiation ( 2 , 19 , 54 ) and which have reported histological changes ( 55 , 56 ).…”

Metabolic response to radiation therapy in cancer

“…Rat hearts treated with a single dose of 2 Gy showed dysregulation of several metabolic proteins isolated from mitochondrial fractions, including proteins involved in the electron transport chain, glycolysis, and lipid metabolism 353 . Interestingly, murine cardiac models of high‐dose radiation have showed downregulation and decreased activity of multiple parts of the electron transport chain, paired with increased activity of pyruvate dehydrogenase E1α 353,354 . These data contrast with observations from irradiated cancer cells, which show a HIF‐1α‐dependent upregulation of mitochondrial complex proteins after comparable doses of X‐rays or gamma irradiation, 184,355 highlighting the differential impact of metabolic reprogramming in cancerous vs normal tissue.…”