Single-dose and fractionated irradiation promote initiation and progression of atherosclerosis and induce an inflammatory plaque phenotype in ApoE(-/-) mice.
OBJECTIVE
Increased risk of atherosclerosis and stroke has been demonstrated in patients receiving radiotherapy for Hodgkin's lymphoma and head-and-neck cancer. We previously showed that 14 Gy to the carotid arteries of hypercholesterolemic ApoE(-/-) mice resulted in accelerated development of macrophage-rich, inflammatory atherosclerotic lesions. Here we investigate whether clinically relevant fractionated irradiation schedules and lower single doses also predispose to an inflammatory plaque phenotype.


METHODS
ApoE(-/-) mice were given 8 or 14 Gy, or 20 x 2.0 Gy in 4 weeks to the neck, and the carotid arteries were subsequently examined for presence of atherosclerotic lesions, plaque size, and phenotype.


RESULTS
At 4 weeks, early atherosclerotic lesions were found in 44% of the mice after single doses of 14 Gy but not in age-matched controls. At 22 to 30 weeks after irradiation there was a twofold increase in the mean number of carotid lesions (8-14 Gy and 20 x 2.0 Gy) and total plaque burden (single doses only), compared with age-matched controls. The majority of lesions seen at 30 to 34 weeks after fractionated irradiation or 14-Gy single doses were granulocyte rich (100% and 63%, respectively), with thrombotic features (90% and 88%), whereas these phenotypes were much less common in age-matched controls or after a single dose of 8 Gy.


CONCLUSIONS
We showed that fractionated irradiation accelerated the development of atherosclerosis in ApoE(-/-) mice and predisposed to the formation of an inflammatory, thrombotic plaque phenotype.
Hoving
Saske
S
Division of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Heeneman
Sylvia
S
Gijbels
Marion J J
MJ
te Poele
Johannes A M
JA
Russell
Nicola S
NS
Daemen
Mat J A P
MJ
Stewart
Fiona A
FA
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000209:etiology* / Q000378:metabolism*; D019583:Dose Fractionation, Radiation; D004307:Dose-Response Relationship, Radiation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011832:Radiation Injuries / Q000209:etiology* / Q000378:metabolism*
D001057:Apolipoproteins E