Protective Role of Peroxisome Proliferator-Activated Receptor-γ in the Development of Intracranial Aneurysm Rupture

Background and Purpose-Inflammation is emerging as a key component of the pathophysiology of intracranial aneurysms. Peroxisome proliferator-activated receptor-gamma (PPAR gamma) is a nuclear hormone receptor of which activation modulates various aspects of inflammation. Methods-Using a mouse model of intracranial aneurysm, we examined the potential roles of PPAR gamma in the development of rupture of intracranial aneurysm. Results-A PPAR gamma agonist, pioglitazone, significantly reduced the incidence of ruptured aneurysms and the rupture rate without affecting the total incidence aneurysm (unruptured aneurysms and ruptured aneurysms). PPAR gamma antagonist (GW9662) abolished the protective effect of pioglitazone. The protective effect of pioglitazone was absent in mice lacking macrophage PPAR gamma. Pioglitazone treatment reduced the mRNA levels of inflammatory cytokines (monocyte chemoattractant factor-1, interleukin-1, and interleukin-6) that are primarily produced by macrophages in the cerebral arteries. Pioglitazone treatment reduced the infiltration of M1 macrophage into the cerebral arteries and the macrophage M1/M2 ratio. Depletion of macrophages significantly reduced the rupture rate. Conclusions-Our data showed that the activation of macrophage PPAR gamma protects against the development of aneurysmal rupture. PPAR gamma in inflammatory cells may be a potential therapeutic target for the prevention of aneurysmal rupture.