Short‐Term Statin Treatment Reduces, and Long‐Term Statin Treatment Abolishes, Chronic Vascular Injury by Radiation Therapy

Abstract

Background The incidental use of statins during radiation therapy has been associated with a reduced long‐term risk of developing atherosclerotic cardiovascular disease. We examined whether irradiation causes chronic vascular injury and whether short‐term administration of statins during and after irradiation is sufficient to prevent chronic injury compared with long‐term administration. Methods and Results C57Bl/6 mice were pretreated with pravastatin for 72 hours and then exposed to 12 Gy X‐ray head‐and‐neck irradiation. Pravastatin was then administered either for an additional 24 hours or for 1 year. Carotid arteries were tested for vascular reactivity, altered gene expression, and collagen deposition 1 year after irradiation. Treatment with pravastatin for 24 hours after irradiation reduced the loss of endothelium‐dependent vasorelaxation and protected against enhanced vasoconstriction. Expression of markers associated with inflammation (NFκB p65 [phospho‐nuclear factor kappa B p65] and TNF‐α [tumor necrosis factor alpha]) and with oxidative stress (NADPH oxidases 2 and 4) were lowered and subunits of the voltage and Ca 2+ activated K + BK channel (potassium calcium‐activated channel subfamily M alpha 1 and potassium calcium‐activated channel subfamily M regulatory beta subunit 1) in the carotid artery were modulated. Treatment with pravastatin for 1 year after irradiation completely reversed irradiation‐induced changes. Conclusions Short‐term administration of pravastatin is sufficient to reduce chronic vascular injury at 1 year after irradiation. Long‐term administration eliminates the effects of irradiation. These findings suggest that a prospective treatment strategy involving statins could be effective in patients undergoing radiation therapy. The optimal duration of treatment in humans has yet to be determined.