Rosiglitazone Protects Endothelial Cells From Irradiation-Induced Mitochondrial Dysfunction.

Bjorn Baselet,An Aerts,Ivo Lambrichts,Ronald B Driesen,Tom Sieprath,Niels Belmans,Emma Coninx,Sarah Baatout,Winnok H De Vos,Pierre Sonveaux

doi:10.3389/fphar.2020.00268

Abstract

Background and PurposeUp to 50–60% of all cancer patients receive radiotherapy as part of their treatment strategy. However, the mechanisms accounting for increased vascular risks after irradiation are not completely understood. Mitochondrial dysfunction has been identified as a potential cause of radiation-induced atherosclerosis.Materials and MethodsAssays for apoptosis, cellular metabolism, mitochondrial DNA content, functionality and morphology were used to compare the response of endothelial cells to a single 2 Gy dose of X-rays under basal conditions or after pharmacological treatments that either reduced (EtBr) or increased (rosiglitazone) mitochondrial content.ResultsExposure to ionizing radiation caused a persistent reduction in mitochondrial content of endothelial cells. Pharmacological reduction of mitochondrial DNA content rendered endothelial cells more vulnerable to radiation-induced apoptosis, whereas rosiglitazone treatment increased oxidative metabolism and redox state and decreased the levels of apoptosis after irradiation.ConclusionPre-existing mitochondrial damage sensitizes endothelial cells to ionizing radiation-induced mitochondrial dysfunction. Rosiglitazone protects endothelial cells from the detrimental effects of radiation exposure on mitochondrial metabolism and oxidative stress. Thus, our findings indicate that rosiglitazone may have potential value as prophylactic for radiation-induced atherosclerosis.

Highlights

High radiation doses (≥2 Gy) are known to increase the risk of cardiovascular diseases (CVD) after radiotherapy (RT) (Hildebrandt, 2010; Shimizu et al, 2010; Darby et al, 2013)
To gain more knowledge about the mitochondrial effects of X-ray irradiation on endothelial cells, we first tested whether irradiation of telomerase-immortalized coronary artery endothelial (TICAE) cells (Figure 1A) constitutively expressing mtGFP with a single 2 Gy X-ray dose induced changes in mitochondrial number during a time span of 98 h after ionizing radiation exposure
To study how preexisting mitochondrial dysfunction can affect TICAE cell response to ionizing radiation exposure, cells were treated either chronically with ethidium bromide to generate for caspase 3/7 activity) and TICAE-EtBr cells

Summary

Introduction

High radiation doses (≥2 Gy) are known to increase the risk of cardiovascular diseases (CVD) after radiotherapy (RT) (Hildebrandt, 2010; Shimizu et al, 2010; Darby et al, 2013). The vascular effects of ionizing radiation are not completely understood, as knowledge of the underlying biological and molecular mechanism. Rosiglitazone Protects Irradiated Endothelial Mitochondria of radiation-induced CVD is currently limited (Little et al, 2008; Hildebrandt, 2010), resulting in possibly inadequate radiation protection. Recent evidence indicates that mitochondria play a crucial role in the cellular and molecular mechanisms underlying atherosclerosis. While minute levels of ROS are crucial for cellular signaling pathways, an excess can lead to a state of oxidative stress, which may drive cells into senescence or trigger apoptosis (Yu et al, 2012; Sieprath et al, 2015). Mitochondrial dysfunction has been identified as a potential cause of radiation-induced atherosclerosis

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Discussion

Conclusion