MiRNA-Mediated Fibrosis in the Out-of-Target Heart following Partial-Body Irradiation

Abstract

Recent reports have shown a link between radiation exposure and non-cancer diseases such as radiation-induced heart disease (RIHD). Radiation exposures are often inhomogeneous, and out-of-target effects have been studied in terms of cancer risk, but very few studies have been carried out for non-cancer diseases. Here, the role of miRNAs in the pathogenesis of RIHD was investigated. C57Bl/6J female mice were whole- (WBI) or partial-body-irradiated (PBI) with 2 Gy of X-rays or sham-irradiated (SI). In PBI exposure, the lower third of the mouse body was irradiated, while the upper two-thirds were shielded. From all groups, hearts were collected 15 days or 6 months post-irradiation. The MiRNome analysis at 15 days post-irradiation showed that miRNAs, belonging to the myomiR family, were highly differentially expressed in WBI and PBI mouse hearts compared with SI hearts. Raman spectral data collected 15 days and 6 months post-irradiation showed biochemical differences among SI, WBI and PBI mouse hearts. Fibrosis in WBI and PBI mouse hearts, indicated by the increased deposition of collagen and the overexpression of genes involved in myofibroblast activation, was found 6 months post-irradiation. Using an in vitro co-culture system, involving directly irradiated skeletal muscle and unirradiated ventricular cardiac human cells, we propose the role of miR-1/133a as mediators of the abscopal response, suggesting that miRNA-based strategies could be relevant for limiting tissue-dependent reactions in non-directly irradiated tissues.

Cancer and Non-Cancer Effects Following Ionizing Irradiation

“…Honaryar et al [ 13 ] conducted a prospective study of 101 breast cancer patients who received radiotherapy but not chemotherapy, and found that at two years after radiotherapy, early progression of calcification in the left anterior descending coronary artery is associated with radiation exposure of the left ventricle. Tanno et al [ 14 ] performed microRNome analysis in the heart of wild-type mice whose whole bodies or partial (lower one-third) bodies were irradiated, and revealed the differential expression of microRNAs belonging to the myomiR family in the heart of whole body- or partial body-irradiated mice. Tanno et al [ 14 ] also conducted in vitro experiments whereby irradiated skeletal muscle cells and non-irradiated ventricular cells were co-cultured, and proposed miR-1/133a as a potential mediator of the abscopal (out-of-field) response in non-directly irradiated tissues.…”

“…Tanno et al [ 14 ] performed microRNome analysis in the heart of wild-type mice whose whole bodies or partial (lower one-third) bodies were irradiated, and revealed the differential expression of microRNAs belonging to the myomiR family in the heart of whole body- or partial body-irradiated mice. Tanno et al [ 14 ] also conducted in vitro experiments whereby irradiated skeletal muscle cells and non-irradiated ventricular cells were co-cultured, and proposed miR-1/133a as a potential mediator of the abscopal (out-of-field) response in non-directly irradiated tissues. Mpweme Bangando et al [ 15 ] irradiated the aortic valves of mice defective in transient receptor potential melastatin 4 (TRPM4, monovalent non-selective cation channel) or their wild-type counterparts, and found that TRPM4 is involved in aortic valve remodeling after irradiation.…”

“…Therefore, this Special Issue ( ) aims to serve as a forum to gather the latest developments and discuss future prospects in the field of normal tissue responses to radiation exposure. The Special Issue consists of 18 articles [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ] outlining the cancer and non-cancer effects of radiation occurring in various tissues (e.g., those in the circulatory, sensory, nervous, respiratory, and reproductive systems), including studies on mitigation strategies and biomarkers, as outlined below.…”

Fibrosis: Types, Effects, Markers, Mechanisms for Disease Progression, and Its Relation with Oxidative Stress, Immunity, and Inflammation

“…About two-thirds of the heart’s cells are fibroblasts, which are located in the connective tissue. They play a role in a variety of cardiac functions, such as controlling the ECM’s equilibrium, rebuilding the ECM, and producing growth factors and cytokines [ 124 ]. The typical role of fibrocyte cells is to secrete collagen and support the heart’s structural integrity.…”

Noncancer Effects of Ionizing Radiation Exposure on the Eye, the Circulatory System and beyond: Developments made since the 2011 ICRP Statement on Tissue Reactions

“…For kidneys, the AHS study has shown an increased radiation risk of chronic kidney disease (CKD) and suggested a role of CKD in CVD development ( 133 ). Studies in rats have shown that targeted kidney irradiation induces remodeling of the nontargeted heart mediated in part by the immune response ( 134 , 135 ), perhaps also by other mechanisms such as microRNAs ( 136 ), suggesting a role of kidney injury in radiogenic heart disease. Considering that CVD risk factors include diabetes and that an increased radiation risk of diabetes have been observed after high dose, fractionated radiotherapy ( 137 – 139 ), the pancreas may be a candidate target, although radiation risk of diabetes at lower dose is uncertain ( 115 ).…”