UNDERSTANDING THE EFFECTS OF CANCER RADIATION THERAPY ON ENDOTHELIAL CELL DYSFUNCTION - THE ROLE OF NF[kappa]B/JNK

UNDERSTANDING THE EFFECTS OF CANCER RADIATION THERAPY ON ENDOTHELIAL CELL DYSFUNCTION - THE ROLE OF NF[kappa]B/JNK

Cardiovascular disease is the principal cause of mortality in developed societies. Studies have identified a correlation between radiotherapy for cancer and atherosclerosis in later life 1 . Endothelial cell dysfunction is a defining feature of atherosclerosis initiation. This study aims to investig...

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Veröffentlicht in:Heart (British Cardiac Society) 2014-12, Vol.100, p.A7
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description Cardiovascular disease is the principal cause of mortality in developed societies. Studies have identified a correlation between radiotherapy for cancer and atherosclerosis in later life 1 . Endothelial cell dysfunction is a defining feature of atherosclerosis initiation. This study aims to investigate the effect of radiation on endothelial cell intracellular signalling networks, including the Nuclear Factor-kappaB (NFκB) and c-Jun N-terminal kinase (JNK) pathways. Human umbilical vein endothelial cells (HUVECs) were exposed to 10 Gy X-rays using an X-RAD 225 biological irradiator. Western blotting was used to detect NFκB and JNK pathway activation in whole cell lysates using anti-phospho-p65, anti-IκBα, anti-tp100/p52 and anti-phospho-JNK antibodies and in nuclear extracts using anti-NFκB-p65 antibodies. An in vitro kinase assay utilising 32P enabled detection of JNK-mediated phosphorylation of c-Jun. X-irradiation induced p65 phosphorylation (fold increase at 2hrs; 2.5±0.42, p
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Studies have identified a correlation between radiotherapy for cancer and atherosclerosis in later life 1 . Endothelial cell dysfunction is a defining feature of atherosclerosis initiation. This study aims to investigate the effect of radiation on endothelial cell intracellular signalling networks, including the Nuclear Factor-kappaB (NFκB) and c-Jun N-terminal kinase (JNK) pathways. Human umbilical vein endothelial cells (HUVECs) were exposed to 10 Gy X-rays using an X-RAD 225 biological irradiator. Western blotting was used to detect NFκB and JNK pathway activation in whole cell lysates using anti-phospho-p65, anti-IκBα, anti-tp100/p52 and anti-phospho-JNK antibodies and in nuclear extracts using anti-NFκB-p65 antibodies. An in vitro kinase assay utilising 32P enabled detection of JNK-mediated phosphorylation of c-Jun. X-irradiation induced p65 phosphorylation (fold increase at 2hrs; 2.5±0.42, p&lt;0.05, n=3) and IκBα degradation (fold at 8hrs; 0.29±0.05, n=3) in HUVECs, markers of canonical NFκB pathway activation. Surprisingly, nuclear p65 levels were not increased suggesting absence of p65 nuclear translocation. Interestingly, tp100/p52 levels were unaltered after irradiation implying that the non-canonical pathway is not activated. X-irradiation also triggered JNK phosphorylation (fold increase at 4hrs; 2.73±0.66, n=3) and JNK kinase activity, observed as increased phosphorylated c-Jun expression 4 hours after irradiation. Thus stress-associated signalling pathways (canonical NFκB and JNK pathways) are activated in irradiated endothelial cells. Further investigations will confirm the cellular events that link radiotherapy and cardiovascular disease. 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