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dc.contributor.authorWu, Haiyan
dc.contributor.authorvan Thiel, Bibi S
dc.contributor.authorBautista-Niño, Paula K
dc.contributor.authorReiling, Erwin
dc.contributor.authorDurik, Matej
dc.contributor.authorLeijten, Frank P J
dc.contributor.authorRidwan, Yanto
dc.contributor.authorBrandt, Renata M C
dc.contributor.authorvan Steeg, Harry
dc.contributor.authorDollé, Martijn E T
dc.contributor.authorVermeij, Wilbert P
dc.contributor.authorHoeijmakers, Jan H J
dc.contributor.authorEssers, Jeroen
dc.contributor.authorvan der Pluijm, Ingrid
dc.contributor.authorDanser, A H Jan
dc.contributor.authorRoks, Anton J M
dc.date.accessioned2018-01-24T13:42:02Z
dc.date.available2018-01-24T13:42:02Z
dc.date.issued2017-08-01
dc.identifier.citationDietary restriction but not angiotensin II type 1 receptor blockade improves DNA damage-related vasodilator dysfunction in rapidly aging Ercc1Δ/- mice. 2017, 131 (15):1941-1953 Clin. Sci.en
dc.identifier.issn1470-8736
dc.identifier.pmid28620011
dc.identifier.doi10.1042/CS20170026
dc.identifier.urihttp://hdl.handle.net/10029/621245
dc.description.abstractDNA 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 potential mechanisms. 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.
dc.language.isoenen
dc.rightsinfo:eu-repo/semantics/closedAccessen
dc.subject.meshAging
dc.subject.meshAngiotensin II
dc.subject.meshAnimals
dc.subject.meshBlood Pressure
dc.subject.meshDNA Damage
dc.subject.meshDNA-Binding Proteins
dc.subject.meshDiet
dc.subject.meshEndonucleases
dc.subject.meshFemale
dc.subject.meshHumans
dc.subject.meshMale
dc.subject.meshMice
dc.subject.meshMice, Knockout
dc.subject.meshNitric Oxide
dc.subject.meshReceptor, Angiotensin, Type 1
dc.subject.meshVascular Diseases
dc.subject.meshVasodilation
dc.titleDietary restriction but not angiotensin II type 1 receptor blockade improves DNA damage-related vasodilator dysfunction in rapidly aging Ercc1Δ/- mice.en
dc.typeArticleen
dc.identifier.journalClin Sci 2017; 131(15):1941-53en
html.description.abstractDNA 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 potential mechanisms. 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.


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