Hyperglycemia Suppresses Calcium Phosphate–Induced Aneurysm Formation Through Inhibition of Macrophage Activation

Background The aim of this study was to elucidate aspects of diabetes mellitus–induced suppression of aneurysm. We hypothesized that high glucose suppresses aneurysm by inhibiting macrophage activation via activation of Nr1h2 (also known as liver X receptor β), recently characterized as a glucose‐sensing nuclear receptor. Methods and Results Calcium phosphate (Ca PO 4 )–induced aneurysm formation was significantly suppressed in the arterial wall in type 1 and 2 diabetic mice. A murine macrophage cell line, RAW 264.7, was treated with tumor necrosis factor α (TNF‐α) plus Ca PO 4 and showed a significant increase in matrix metalloproteinase 9 (Mmp9) mRNA and secreted protein expression compared with TNF‐ α alone. Elevated Mmp9 expression was significantly suppressed by hyperglycemic conditions (15.5 mmol/L glucose) compared with normoglycemic conditions (5.5 mmol/L glucose) or normoglycemic conditions with high osmotic pressure (5.5 mmol/L glucose +10.0 mmol/L mannitol). Nr1h2 mRNA and protein expression were suppressed by treatment with TNF‐ α plus Ca PO 4 but were restored by hyperglycemic conditions. Activation of Nr1h2 by the antagonist GW 3965 during stimulation with TNF‐ α plus Ca PO 4 mimicked hyperglycemic conditions and inhibited Mmp9 upregulation, whereas the deactivation of Nr1h2 by small interfering RNA (si RNA) under hyperglycemic conditions canceled the suppressive effect and restored Mmp9 expression induced by TNF‐ α plus Ca PO 4 . Moreover, Nr1h2 activation with GW 3965 significantly suppressed Ca PO 4 ‐induced aneurysm in mice compared with vehicle‐injected control mice. Conclusions Our results show that hyperglycemia suppresses macrophage activation and aneurysmal degeneration through the activation of Nr1h2. Although further validation of the underlying pathway is necessary, targeting Nr1h2 is a potential therapeutic approach to treating aneurysm.