Role of TGF Beta and PPAR Alpha Signaling Pathways in Radiation Response of Locally Exposed Heart: Integrated Global Transcriptomics and Proteomics Analysis

Epidemiological
data from patients undergoing radiotherapy for
thoracic tumors clearly show the damaging effect of ionizing radiation
on cardiovascular system. The long-term impairment of heart function
and structure after local high-dose irradiation is associated with
systemic inflammatory response, contraction impairment, microvascular
damage, and cardiac fibrosis. The goal of the present study was to
investigate molecular mechanisms involved in this process. C57BL/6J
mice received a single X-ray dose of 16 Gy given locally to the heart
at the age of 8 weeks. Radiation-induced changes in the heart transcriptome
and proteome were investigated 40 weeks after the exposure. The omics
data were analyzed by bioinformatics tools and validated by immunoblotting.
Integrated network analysis of transcriptomics and proteomics data
elucidated the signaling pathways that were similarly affected at
gene and protein level. Analysis showed induction of transforming
growth factor (TGF) beta signaling but inactivation of peroxisome
proliferator-activated receptor (PPAR) alpha signaling in irradiated
heart. The putative mediator role of mitogen-activated protein kinase
cascade linking PPAR alpha and TGF beta signaling was supported by
data from immunoblotting and ELISA. This study indicates that both
signaling pathways are involved in radiation-induced heart fibrosis,
metabolic disordering, and impaired contractility, a pathophysiological
condition that is often observed in patients that received high radiation
doses in thorax.