Abstract 510: Dietary Restriction Improves Vasodilator Dysfunction Caused by Accelerated Vascular Aging Due to Genomic Instability

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Abstract

Objective Recently we discovered that genomic instability is associated with accelerated vascular aging in humans and mouse models, and that DNA repair-defective mice (ERCC1-/Δ7) display accelerated age-dependent deterioration of endothelium-dependent and vascular smooth muscle dilator function (Durik M. et al. Circulation 2012).Dietary restriction (DR) is known to slow aging. We explored whether DR would inhibit accelerated vascular aging caused by genomic instability by measuring vasodilator function in both male and female ERCC1-/Δ7 mice vs. wild-type (WT) littermates.

Methods WT and ERCC1-/Δ7 were fed with DR (increasing 10 to 30% nutrient restriction) or ad libitum (AL) diets for 9 weeks, whereafterthoracic aortas were isolated and used for ex vivo organ bath experiments. To investigate endothelial and vascular smooth muscle dilator function, aorta preconstricted with U44619 (thromboxane analogue) was exposed to acetylcholine (Ach: 10-9-10-5M) and sodium nitroprusside (SNP: 10-9-10-4M), respectively. Maximal dilator responses (mean+/-SEM) are shown between brackets, and were calculated as % decrease of precontraction. Significance values are those of dose-related responses tested by general linear model for repeated measures.

Results In ERCC1-/Δ7 mice fed AL both ACh and SNP responses were significantly smaller than in WT (Ach: 66.89+/-8.9% (n=8) vs. 41.45+/-4.74% (n=11); SNP: 80.27+/-4.89% (n=5) vs.59.35+/-3.32% (n=5), p<0.0001, WT vs. ERCC1-/Δ7) with no gender differences. Whilst without effect in WT, DR normalized the SNP responses of ERCC1-/Δ7 (79.60+/-7.09% (n=6)) to that of WT gender-independently. ACh responses were also improved (from 41.45+/-4.74% AL (n=11) to 56.02+/-4.73% DR (n=11)), but most pronounced in female ERCC1-/Δ7 (38.33+/-8.39% AL (n=4) vs. -67.31+/-6.22% DR (n=4), p<0.0001).

Conclusion In ERCC1-/Δ7 mice, DR improved vasodilator response in both genders. Endothelial function might be improved only efficiently in female mice, whilst the NO-mediated dilation of VSMC is improved equally well in both genders. Therefore, DR is beneficial for vascular function during vascular aging caused by genomic instability, and its impact on EC versus VSMC appears to be gender-dependent.

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