Dietary restriction but not angiotensin II type 1 receptor blockade improves DNA damage-related vasodilator dysfunction in rapidly aging Ercc1Δ/- mice

Haiyan Wu, Bibi S van Thiel, Paula K Bautista-Niño, Erwin Reiling, Matej Durik, Frank P J Leijten, Yanto Ridwan, Renata M C Brandt, Harry van Steeg, Martijn E T Dollé, Wilbert P Vermeij, Jan H J Hoeijmakers, Jeroen Essers, Ingrid van der Pluijm, A H Jan Danser, Anton J M Roks

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

Abstract

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 (Ercc1Δ/-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 (RAS). Ercc1Δ/- mice showed increased blood pressure and decreased aortic relaxations to acetylcholine (ACh) in organ bath experiments. Nitric oxide (NO) signaling and phospho-Ser1177-eNOS were compromised in Ercc1Δ/- DR improved relaxations by increasing prostaglandin-mediated responses. Increase of cyclo-oxygenase 2 and decrease of phosphodiesterase 4B were identified as potentialmechanisms. DR also prevented loss of NO signaling in vascular smooth muscle cells and normalized angiotensin II (Ang II) vasoconstrictions, which were increased in Ercc1Δ/- mice. Ercc1Δ/- mutants showed a loss of Ang II type 2 receptor-mediated counter-regulation of Ang 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 efficacy of RAS blockade with respect to endothelial function improvement. In summary, DR effectively prevents endothelium-dependent vasodilator dysfunction by augmenting prostaglandin-mediated responses, whereas chronic Ang II type 1 receptor blockade is ineffective.
Original languageEnglish
Pages (from-to)1941-1953
Number of pages13
JournalClinical science (London, England : 1979)
Volume131
Issue number15
DOIs
Publication statusPublished - 1 Aug 2017
Externally publishedYes

Keywords

  • Aging/genetics
  • Angiotensin II/metabolism
  • Animals
  • Blood Pressure
  • DNA Damage
  • DNA-Binding Proteins/genetics
  • Diet
  • Endonucleases/genetics
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Nitric Oxide/metabolism
  • Receptor, Angiotensin, Type 1/genetics
  • Vascular Diseases/diet therapy
  • Vasodilation

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