Roles of Sirtuin-1 in the Prevention of Intracranial Aneurysm Rupture in Mice

Given that pathways regulated by SIRT1 are implicated in the pathophysiology of intracranial aneurysms, we hypothesized that activation and overexpression of SIRT1 prevent aneurysm rupture by suppressing vascular inflammation. METHODS: Intracranial aneurysms were induced in mice by systemic hypertension and a single intracisternal injection of elastase. We analyzed the expression of SIRT1 in human and mouse aneurysms. We investigated the role of SIRT1 in aneurysm rupture using genetic overexpression of SIRT1 and cell-specific deletion in the endothelial, vascular smooth muscle, and myeloid lineages. We administered a SIRT1 activator and a SIRT1 inhibitor to assess the rupture rate and mRNA expression in cerebral arteries. RESULTS: SIRT1 expression was significantly lower in intracranial aneurysm tissues than in control cerebral arteries in mice, with a similar trend in human aneurysms. Global overexpression of SIRT1 significantly decreased the rupture rate. Endothelial SIRT1 deletion increased the rupture rate, with no effect observed in other cell types. Inhibition of SIRT1 increased the rupture rate, whereas SIRT1 activation reduced the rupture rate and suppressed mRNA expression of proinflammatory cytokines in cerebral arteries. CONCLUSIONS: Our findings support a protective role of SIRT1 against intracranial aneurysm rupture in mice, with endothelial SIRT1 playing an important role in aneurysm stabilization. Pharmacological SIRT1 activation reduced aneurysm rupture and was associated with reduced vascular inflammation, providing a preclinical rationale for further investigation of SIRT1-related pathways.