Pravastatin limits endothelial activation after irradiation and decreases the resulting inflammatory and thrombotic responses.
Endothelial dysfunction has been implicated in the pathogenesis of atherosclerosis, fibrosis and vascular occlusion after radiation therapy. Statins have been reported to improve endothelial function; however, this beneficial effect on endothelial cells has never been investigated after irradiation. Therefore, using human microvascular endothelial cells from lung that had been irradiated with 5 or 10 Gy, we assessed the effect of pravastatin on endothelial activation by ELISA, cell-ELISA and electrophoretic mobility shift assay and increased blood-endothelial cell interactions by a flow adhesion assay. Pravastatin inhibited the overproduction of monocyte chemoattractant protein 1, IL6 and IL8 and the enhanced expression of intercellular adhesion molecule 1 but had no effect on platelet-endothelial cell adhesion molecule 1 expression. Moreover, pravastatin down-regulated the radiation-induced activation of the transcription factor activator protein 1 but not of nuclear factor-kappaB. Finally, an inhibition by pravastatin of increased adhesion of leukocytes and platelets to irradiated endothelial cells was observed. The effect of pravastatin was maintained up to 14 days after irradiation and was reversed by mevalonate. Pravastatin exerts persistent anti-inflammatory and anti-thrombotic effects on irradiated endothelial cells. Statins may be considered in therapeutic strategies for the management of patients treated with radiation therapy.
Gaugler
Marie-Hélène
MH
Institut de Radioprotection et de Sûreté Nucléaire, IRSN/DRPH/SRBE, F-92262 Fontenay-aux-Roses Cedex, France. marie-helene.gaugler@irsn.fr
Vereycken-Holler
Valérie
V
Squiban
Claire
C
Vandamme
Marie
M
Vozenin-Brotons
Marie-Catherine
MC
Benderitter
Marc
M
D001161:Arteriosclerosis / Q000188:drug therapy / Q000209:etiology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D008798:Mevalonic Acid / Q000494:pharmacology; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D017035:Pravastatin / Q000494:pharmacology*; D011878:Radiotherapy / Q000009:adverse effects*; D013927:Thrombosis / Q000517:prevention & control*
C111835:CCL2 protein, human; D018932:Chemokine CCL2; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D018799:Intercellular Adhesion Molecule-1; D017035:Pravastatin; D008798:Mevalonic Acid