Dietary restriction but not angiotensin II type 1 receptor blockade improves DNA damage-related vasodilator dysfunction in rapidly aging Ercc1{Delta}/-mice

DNA damage is an important contributor to endothelial dysfunction and age-related vascular disease. Recently, we demonstrated in a DNA repair-deficient, prematurely aging mouse model ( Ercc1/- mice) that dietary restriction (DR) strongly increases life- and health span, including ameliorating endothelial dysfunction, by preserving genomic integrity. In this mouse mutant displaying prominent accelerated, age-dependent endothelial dysfunction we investigated the signaling pathways involved in improved endothelium-mediated vasodilation by DR, and explore the potential role of the renin-angiotensin system . Ercc1/- mice showed increased blood pressure and decreased aortic relaxations to acetylcholine in organ bath experiments. Nitric oxide (NO) signaling and phospho-Ser1177-eNOS were compromised in Ercc1d/-. DR improved relaxations by increasing prostaglandin-mediated responses. Increase of cyclo-oxygenase 2 and decrease of phosphodiesterase 4B were identified as potential mechanisms. DR also prevented loss of NO signaling in vascular smooth muscle cells and normalized angiotensin II vasoconstrictions, which were increased in Ercc1/- mice. Ercc1/- mutants showed a loss of Angiotensin II type 2 receptor-mediated counterregulation of Angiotensin II type 1 receptor-induced vasoconstrictions. Chronic losartan treatment effectively decreased blood pressure, but did not improve endothelium-dependent relaxations. This result might relate to the aging-associated loss of treatment e...

Source: Clinical Science - June 15, 2017 Category: Biomedical Science Authors: Wu, H., van Thiel, B. S., Bautista-Nino, P. K., Reiling, E., Durik, M., Leijten, F. P. J., Ridwan, Y., Brandt, R. M. C., van Steeg, H., Dolle, M. E. T., Vermeij, W. P., Hoeijmakers, J. H. J., Essers, J., van der Pluijm, I., Danser, A. H. J., Roks, A. J. M Tags: PublishAheadOfPrint Source Type: research