Pravastatin Limits Endothelial Activation after Irradiation and Decreases the Resulting Inflammatory and Thrombotic Responses

Abstract

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.

Simvastatin Ameliorates Radiation Enteropathy Development After Localized, Fractionated Irradiation by a Protein C-Independent Mechanism

“…Statins exert anti-inflammatory and anti-thrombotic effects on irradiated endothelial cells in vitro (40) and reduce lung injury in mice after irradiation of the chest (41).…”

Pravastatin Reduces Radiation-Induced Damage to Normal Tissues

“…Statins are HMG-CoA reductase inhibitors that are widely used to treat hypercholesterolemia; their potential radioprotective effects have been discussed in a limited number of preclinical and clinical studies (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). Clinical studies have reported that pravastatin has anti-inflammatory effects and is a safe HMG-CoA reductase inhibitor that is water soluble (5).…”

“…Statins have previously been reported to have beneficial effects on radiation-induced toxicities, and numerous studies have demonstrated the anti-inflammatory effects of pravastatin following radiation exposure (7)(8)(9)(10)(11)(12)(13)(14)(15). Previous clinical data has shown that the use of statins reduces acute gastrointestinal symptoms following radical pelvic radiotherapy (15).…”

“…However, the mechanism of the radio protective effect of statins remains unclear. In addition, only a few experimental studies have reported the radioprotective effects of pravastatin and these remain to be completely elucidated (7)(8)(9)(10).…”

Radiothérapie : quelles orientations thérapeutiques contre les séquelles digestives ?

“…Ainsi, la pravastatine est capable, in vitro sur cellules endothéliales microvasculaires humaines, d'inhiber l'adhésion leucocytaire et plaquettaire induite par l'irradiation [15]. Une étude réalisée in vitro sur cellules endothéliales macrovasculaires humaines montre que la lovastatine protège les cellules de l'apoptose radioinduite [16].…”