Universität zu Köln

Wu, Haiyan, van Thiel, Bibi S., Bautista-Nino, Paula K., Reiling, Erwin, Durik, Matej ORCID: 0000-0003-1023-919X, Leijten, Frank P. J., Ridwan, Yanto, Brandt, Renata M. C., van Steeg, Harry, Dolle, Martijn E. T., Vermeij, Wilbert P., Hoeijmakers, Jan H. J., Essers, Jeroen, van der Pluijm, Ingrid, Danser, A. H. Jan and Roks, Anton J. M. (2017). Dietary restriction but not angiotensin II type 1 receptor blockade improves DNA damage-related vasodilator dysfunction in rapidly aging Ercc1(Delta/-) mice. Clin. Sci., 131 (15). S. 1941 - 1954. LONDON: PORTLAND PRESS LTD. ISSN 1470-8736

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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 (Ercc1(Delta/-) 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). Ercc1(Delta/-) 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 Ercc1(Delta/-). 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 Ercc1(Delta/-) mice. Ercc1(Delta/-)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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Wu, Haiyan UNSPECIFIED UNSPECIFIED UNSPECIFIED van Thiel, Bibi S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bautista-Nino, Paula K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Reiling, Erwin UNSPECIFIED UNSPECIFIED UNSPECIFIED Durik, Matej UNSPECIFIED orcid.org/0000-0003-1023-919X UNSPECIFIED Leijten, Frank P. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ridwan, Yanto UNSPECIFIED UNSPECIFIED UNSPECIFIED Brandt, Renata M. C. UNSPECIFIED UNSPECIFIED UNSPECIFIED van Steeg, Harry UNSPECIFIED UNSPECIFIED UNSPECIFIED Dolle, Martijn E. T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Vermeij, Wilbert P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoeijmakers, Jan H. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Essers, Jeroen UNSPECIFIED UNSPECIFIED UNSPECIFIED van der Pluijm, Ingrid UNSPECIFIED UNSPECIFIED UNSPECIFIED Danser, A. H. Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED Roks, Anton J. M. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-223518
DOI:	10.1042/CS20170026
Journal or Publication Title:	Clin. Sci.
Volume:	131
Number:	15
Page Range:	S. 1941 - 1954
Date:	2017
Publisher:	PORTLAND PRESS LTD
Place of Publication:	LONDON
ISSN:	1470-8736
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ENDOTHELIAL DYSFUNCTION; MEDIATED VASODILATION; CALORIC RESTRICTION; BLOOD-PRESSURE; NITRIC-OXIDE; AGE; EXPRESSION; RENIN; ALDOSTERONE; DETERMINANT Multiple languages Medicine, Research & Experimental Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/22351