Assessment of Functional Enrichment of Genes Associated with Radiation Cardiosensitivity in Rat Pre-Clinical Models in Human Genome-wide Association Study (GWAS) of Heart Failure

Abstract

enrichment for multiple Ifn transcription factors in fibroblasts (p < 10-21), but not in endothelium. Because radiation might elicit specific damage associated molecular pattern (DAMP) signaling, we hypothesized that this Ifn signaling resulted from cGAS/STING activation following DNA damage. Indeed, RT-PCR for Irf7 in cardiac fibroblasts from wild-type and Mavs-/-(which are deficient in RNA mediated DAMP recognition) mice showed strong activation (p < 0.001 compared to sham XRT), but Cgas-/animals lacked this response (p Z NS compared to sham XRT, p < 0.001 compared to wild-type and Mavs-/after XRT). Cgas-/-(HR Z 0.40, p Z 0.034) and Tmem173-/-(HR Z 0.15, p Z 0.002) animals had significantly improved survival after cardiac XRT as compared to wild-type mice, while Ifnar-/animals showed a trend for improvement as well (HR Z 0.47, p Z 0.094). Histopathologic analysis of cardiac tissues at time of death revealed consistent widespread atrial and ventricular mural thrombus formation and cardiomyocyte atrophy in irradiated wild-type animals, but markedly reduced in Tmem173-/counterparts. Conclusion: Our system establishes a contemporary, genetically defined mouse model of XRT-induced cardiac toxicity. In doing so, we find cardiac irradiation elicits cGAS/STING-(and not MAVS-) dependent, delayed, chronic interferon activation in cardiac fibroblasts. Eliminating this signaling rescues radiation induced cardiac toxicity and improves survival. Inhibitors the cGAS/STING pathway are soon to begin early stage clinical trials and may be candidate drugs for mitigation of late cardiac toxicity following radiotherapy.