TLR4—A Pertinent Player in Radiation-Induced Heart Disease?

Abstract

The heart is one of the organs that is sensitive to developing delayed adverse effects of ionizing radiation (IR) exposure. Radiation-induced heart disease (RIHD) occurs in cancer patients and cancer survivors, as a side effect of radiation therapy of the chest, with manifestation several years post-radiotherapy. Moreover, the continued threat of nuclear bombs or terrorist attacks puts deployed military service members at risk of exposure to total or partial body irradiation. Individuals who survive acute injury from IR will experience delayed adverse effects that include fibrosis and chronic dysfunction of organ systems such as the heart within months to years after radiation exposure. Toll-like receptor 4 (TLR4) is an innate immune receptor that is implicated in several cardiovascular diseases. Studies in preclinical models have established the role of TLR4 as a driver of inflammation and associated cardiac fibrosis and dysfunction using transgenic models. This review explores the relevance of the TLR4 signaling pathway in radiation-induced inflammation and oxidative stress in acute as well as late effects on the heart tissue and the potential for the development of TLR4 inhibitors as a therapeutic target to treat or alleviate RIHD.

Integrative analyses and validation of ferroptosis-related genes and mechanisms associated with cerebrovascular and cardiovascular ischemic diseases

“…TLR4 exhibits the greatest expression among cardiac TLRs, Research has indicated that blocking the TLR4 signaling pathway can decrease the inflammatory response in heart muscle and potentially protect against further harm to the already injured myocardium [ 52 ]. Preclinical research has utilized genetically modified animal models to investigate the involvement of TLR4 in promoting inflammation and development of cardiac fibrosis and dysfunction [ 53 ]. Additionally, investigations have shown that during stroke, molecules typically contained within cells are released into the extracellular space owing to uncontrolled cell death.…”

Mobitz II Atrioventricular Block Following Intracardiac Radiation to the Right Ventricular Outflow Tract

“…There is currently no medical therapy in use to prevent or treat RIHD, but a recent study has found that toll-like receptor 4 (TLR4) is upregulated in RIHD and leads to increased oxidative stress, ECG abnormalities, and abnormal tissue fibrosis and remodeling and postulated that use of a TLR4 inhibitor might alleviate RIHD [ 6 ]. The significance of toll-like receptors in RIHD was also noted in a study that found dexrazoxane (DZR), a medication currently used to prevent cardiotoxicity in patients receiving an anthracycline, significantly reduced expression of IKBKE, MAP3K8, NFKBIA, and TLR5, four genes involved in the toll-like receptor pathway, in irradiated cardiac tissue from rat models that received DZR in combination with RT compared to RT alone [ 7 ].…”