Abstract MP55: Endothelial Sirtuin-1 Deficiency Promotes the Rupture of Intracranial Aneurysm

Abstract

Background: Sirtuin-1 is highly expressed in vascular tissues and plays an important role in numerous metabolic and inflammatory processes. Age-related reduction in Sirtuin-1 expression has been linked to chronic vascular inflammation and senescence, and may explain the increased risk of aneurysm rupture seen in the elderly population. Our previous study showed that pharmacological inhibition of Sirtuin-1 increases the rate of aneurysm rupture. This suggests that Sirtuin-1 protects against the rupture of intracranial aneurysm. However, the cell type responsible for this effect has not been determined. Hypothesis: We hypothesize that reduced expression of Sirtuin-1 in endothelial cells promotes the rupture of intracranial aneurysm. Methods: We induced intracranial aneurysms in mice by combining systemic hypertension and a single injection of elastase into the cerebrospinal fluid. We induced aneurysms in tamoxifen-inducible vascular smooth muscle cell-specific Sirtuin-1 knockout mice (SIRT1 f/f MYH11 ER-Cre+ ) and in endothelial cell-specific Sirtuin-1 knockout mice and their littermates (SIRT1 f/f Tie2 Cre+ , SIRT1 f/f Tie2 Cre- ). We used the rate of aneurysm rupture as the primary endpoint. Results: Smooth muscle cell-specific Sirtuin-1 knockout had no effect on rate of aneurysm rupture. In contrast, SIRT1 f/f Tie2 Cre+ mice experienced a significantly increased rate of aneurysm rupture (SIRT1 f/f Tie2 Cre+ vs. SIRT1 f/f Tie2 Cre- : 86% vs. 42%, P < 0.05). Conclusions: Our findings suggest that Sirtuin-1 expressed in the endothelium, but not in smooth muscle cells, protects against the rupture of intracranial aneurysm. As Tie2 is also expressed in hematopoietic cells, we are conducting experiments using SIRT1 f/f LysM Cre+ mice to exclude potential contributions of hematopoietic Sirtuin-1 to the observed effects. Endothelial Sirtuin-1 may be used as a therapeutic target for preventing the rupture of intracranial aneurysm.