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

Abstract

Thoracic radiotherapy increases the risk of radiation-induced heart damage (riHd); however, the molecular mechanisms underlying these changes are not fully understood. The aim of the present study was to investigate the effects of radiation on the mouse heart using high-throughput proteomics. Male c57Bl/6J mice were used to establish a model of riHd by exposing the entire heart to 16 Gy high-energy X-rays, and cardiac injuries were verified using a cardiac echocardiogram, as well as by measuring serum brain natriuretic peptide levels and conducting H&e and Masson staining 5 months after irradiation. Proteomics experiments were performed using the heart apex of 5-month irradiated mice and control mice that underwent sham-irradiation. The most significantly differentially expressed proteins were enriched in 'cardiac fibrosis' and 'energy metabolism'. Next, the cardiac fibrosis and changes to energy metabolism were confirmed using immunohistochemistry staining and western blotting. extracellular matrix proteins, such as collagen type 1 α 1 chain, collagen type iii α 1 chain, vimentin and cccTc-binding factor, along with metabolism-related proteins, such as fatty acid synthase and solute carrier family 25 member 1, exhibited upregulated expression following exposure to ionizing radiation. additionally, the myocardial mitochondria inner membranes were injured, along with a decrease in aTP levels and the accumulation of lactic acid in the irradiated heart tissues. These results suggest that the high doses of ionizing radiation used lead to structural remodeling, functional injury and fibrotic alterations in the mouse heart. Radiation-induced mitochondrial damage and metabolic alterations of the cardiac tissue may thus be a pathogenic mechanism of riHd.

TRPM4 Participates in Irradiation-Induced Aortic Valve Remodeling in Mice

“…To support this hypothesis, it was shown that cardiac mitochondrial respiratory capacity was reduced 40 weeks after cardiac irradiation in mice at 2 Gy [ 36 ]. Note that this was confirmed in a recent study in mice after heart irradiation at 16 Gy which induces an increase in extracellular matrix proteins and variation in metabolism-related proteins detectable after 5 months, a time similar to that used in our study [ 23 ]. Dysregulation of the metabolism status with modification of ATP levels may impact TRPM4 in two different ways.…”

“…This is a specificity of our study since a recent review reported that among 159 studies using models of irradiation-induced cardiac remodeling in rodents, only 4% targeted a restricted area of the heart while others undertook whole heart or whole animal irradiation [ 26 ]. Some of these studies in mice with specific irradiation of the heart revealed an increase in fibrosis detected by Masson trichrome staining, observed at 5 months at the ventricular level [ 23 , 25 ], which was also reported in rats [ 27 ]. Interestingly, in our study, we did not observe such fibrosis neither at the ventricular level nor at the atrial level, while it was present in valvular structures, consistent with a specific targeting of the valve.…”

“…Our animal model of valvular irradiation reproduces several types of valvular damage observed in patients after radiotherapy (stenosis and fibrosis) [ 2 ]. The specific targeting of the aortic valve in our model differs from previously reported studies in mice in which either the entire heart or even animal was irradiated [ 23 , 24 ] or the beam was restricted to the ventricular apex [ 25 ]. This is a specificity of our study since a recent review reported that among 159 studies using models of irradiation-induced cardiac remodeling in rodents, only 4% targeted a restricted area of the heart while others undertook whole heart or whole animal irradiation [ 26 ].…”

Acetylation of Atp5f1c Mediates Cardiomyocyte Senescence via Metabolic Dysfunction in Radiation-Induced Heart Damage

“…Subsequent subcellular localization and functional enrichment analyses via acetyl-proteomics indicated that DEPs at different acetylated sites were enriched in mitochondrial and energy metabolism. Interestingly, we previously discovered that irradiated heart tissue exhibited significant dysregulation of mitochondrial damage and metabolites [ 38 ]. In addition to the myocardium, radiation-induced mitochondrial damage in the skeletal muscle alters the proteins involved in energy metabolism-related processes [ 52 ].…”

“…In our previous study, we found that high-energy X-rays resulted in cardiometabolic disorders, collagen deposition, and suppressed cardiac function [ 38 ]. In this study, we aimed to investigate the mechanisms of radiation-induced cellular senescence, mainly using tandem mass tags- (TMT-) labeled acetylation proteomics.…”