Reactive oxygen species modulate growth of cerebral aneurysms: a study using the free radical scavenger edaravone and p47phox-/- mice

Cerebral aneurysm (CA) is a relatively common disease and can cause a catastrophic subarachnoid hemorrhage with a high mortality and morbidity rate. Despite its clinical and social importance, the detailed mechanism of CA formation remains to be elucidated, resulting in the absence of effective medical treatment against CAs. Recent studies revealed that chronic inflammation in arterial walls by hemodynamic force is implicated in CA formation. Reactive oxygen species (ROS) are a major mediator of inflammation and actively participate in the pathogenesis of various vascular diseases. In the present study, we first assessed the expression of ROS-producing and-eliminating genes in CA walls by immunohistochemistry and RT-PCR analysis. The ROS-producing gene, p47phox, was upregulated in infiltrating macrophages and medial smooth muscle cells in arterial walls. Upregulated ROS-producing genes and suppressed ROS-eliminating genes suggested that ROS overproduction occurred in aneurysmal walls. In situ superoxide imaging by dihydroethidium, which showed ROS overproduction in aneurysmal walls, confirmed this hypothesis. Edaravone, a powerful free radical scavenger, effectively inhibited CA formation by suppressing inflammation-related gene expression in aneurysmal walls. Furthermore, CA formation was markedly inhibited by p47phox deletion in mice and was accompanied by decreased inflammation in aneurysmal walls. These data suggested the active participation of ROS and p47phox in CA formation and the therapeutic potential of an ROS-eliminating agent against CA formation. Laboratory Investigation (2009) 89, 730-741; doi:10.1038/labinvest.2009.36; published online 20 April 2009