Abstract 3684: Short-term Caloric Restriction Reverses Age-associated Vascular Endothelial Dysfunction in Older Mice

Abstract

Backgound: Oxidative stress-mediated, nitric oxide (NO)-dependent vascular endothelial dysfunction develops with aging, increasing the risk of cardiovascular diseases. As such, it is important to identify interventions that can prevent/restore the loss of endothelial function with aging. Caloric restriction (CR) is associated with several physiological benefits and increased longevity in rodents. Some of these benefits are linked to increases in SIRT-1, an enzyme activating endothelial NO synthase (eNOS), and reductions in oxidative stress. We tested the hypothesis that short-term CR would restore vascular endothelial function by improving NO bioavailability and reducing oxidative stress in old B6D2F1-mice, and that this would be associated with increased expression of SIRT-1 and eNOS. Methods: Old (30 months) male B6D2F1-mice were either fed ad libitum (AL, n=6) or were restricted to 70% (3.2g) of their normal food intake for 6 weeks after 2 weeks of progressive restriction (n=6). Carotid artery dilation was assessed ex vivo in response to the endothelium-dependent dilator acetylcholine (ACh) [before and after incubation with the eNOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) or the superoxide dismutase mimetic, TEMPOL] and the endothelium-independent dilator sodium nitroprusside (SNP). Results: ACh-induced dilation was markedly impaired in the AL mice, but was completely restored in the CR mice (63±10% vs. 98±1%, P<0.01). L-NAME decreased ACh dilation by 97% in CR, but only 56% in AL mice, indicating increased NO bioavailability in the CR mice. TEMPOL restored ACh-mediated dilation in AL mice (to 97±1%), but had no effect in CR mice. Aortic protein expression of SIRT-1 and eNOS (western blotting) were 80 –90% higher in CR vs. AL mice (eNOS: 1.9±0.1 vs. 1.0±0.4 P<0.05; SIRT-1: 1.8±0.2 vs. 1.0±0.2, P=0.05). Dilation to SNP was similar in the CR and AL mice (97±1% vs. 96±2%, P=0.63). Conclusion: Short-term CR selectively restores endothelium-dependent dilation in older B6D2F1-mice by increasing NO bioavailability and reducing oxidative stress. These effects are associated with increased vascular expression of SIRT-1 and eNOS. CR may be an effective intervention for reversing age-associated vascular endothelial dysfunction.