SIRT1 Activation with SRT1720 Reverses Impaired Endothelium‐Dependent Dilation in Old Mice by Augmenting COX‐2 Mediated Vasodilation

Abstract

Endothelial dysfunction develops with aging due to reductions in nitric oxide (NO)‐ and/or cyclooxygenase (COX)‐related vasodilation. Treatment with SRT1720 (Sirtris) increases arterial SIRT1 activity and restores endothelium‐dependent dilation (EDD) independent of NO. We hypothesized that COX‐2 vasodilators mediate the improvements in EDD with SRT1720 treatment. Old mice (29–32 mo) were treated with SRT1720 (100 mg/kg BW; OS) or vehicle (OV) for 4 weeks. Maximal ex vivo carotid artery EDD to acetylcholine was reduced with age (Young, 4–9 mo [Y]: 95±1% vs OV: 83±3%, p<0.01) and rescued with SRT1720 (OS: 95±1%, p<0.01). Inhibition of COX‐1 & −2 (indomethacin) reduced max EDD in Y (88±3%, p<0.01) and OS (82±6%, p<0.01), but not in OV (p=0.55), abolishing all group differences (p=0.64). Inhibition of COX‐2 (NS‐398) reduced max EDD in OS (82±6%, p<0.01), but not in Y or OV (p>0.05), and abolished SRT1720 treatment differences (p=0.69). Aortic COX‐2 protein was reduced with age (Y: 0.9±0.2 AU vs OV: 0.5±0.1 AU, p=0.06) and restored with SRT1720 (OS: 1.1±0.2, p<0.05). COX‐1 protein was not different between groups (p=0.23). These results demonstrate that aging is associated with a reduction in COX mediated EDD. SIRT1 activation reverses vascular endothelial dysfunction with aging via COX‐2 specific vasodilators. These results suggest a novel protective effect of SRT1720 treatment on the aged arterial endothelium.