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Lack of vitamin D receptor causes stress-induced premature senescence in vascular smooth muscle cells through enhanced local angiotensin-II signals

Valcheva, P., Cardus Figueras, Ana, Panizo, S., Parisi, E., Bozic, M., Lopez Novoa, J. M., Dusso, A., Fernandez, E. and Valdivielso, J. M. 2014. Lack of vitamin D receptor causes stress-induced premature senescence in vascular smooth muscle cells through enhanced local angiotensin-II signals. Atherosclerosis 235 (2) , pp. 247-255. 10.1016/j.atherosclerosis.2014.05.911

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Abstract

Objectives The inhibition of the renal renin-angiotensin system by the active form of vitamin D contributes to the cardiovascular health benefits of a normal vitamin D status. Local production of angiotensin-II in the vascular wall is a potent mediator of oxidative stress, prompting premature senescence. Herein, our objective was to examine the impact of defective vitamin D signalling on local angiotensin-II levels and arterial health. Methods Primary cultures of aortic vascular smooth muscle cells (VSMC) from wild-type and vitamin D receptor-knockout (VDRKO) mice were used for the assessment of cell growth, angiotensin-II and superoxide anion production and expression levels of cathepsin D, angiotensin-II type 1 receptor and p57Kip2. The in vitro findings were confirmed histologically in aortas from wild-type and VDRKO mice. Results VSMC from VDRKO mice produced more angiotensin-II in culture, and elicited higher levels of cathepsin D, an enzyme with renin-like activity, and angiotensin-II type 1 receptor, than wild-type mice. Accordingly, VDRKO VSMC showed higher intracellular superoxide anion production, which could be suppressed by cathepsin D, angiotensin-II type 1 receptor or NADPH oxidase antagonists. VDRKO cells presented higher levels of p57Kip2, impaired proliferation and premature senescence, all of them blunted upon inhibition of angiotensin-II signalling. In vivo studies confirmed higher levels of cathepsin D, angiotensin-II type 1 receptor and p57Kip2 in aortas from VDRKO mice. Conclusion The beneficial effects of active vitamin D in vascular health could be a result of the attenuation of local production of angiotensin-II and downstream free radicals, thus preventing the premature senescence of VSMC.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Uncontrolled Keywords: VSMC; Vitamin D; Angiotensin-II; ROS; Senescence
Publisher: Elsevier
ISSN: 0021-9150
Date of First Compliant Deposit: 17 May 2017
Date of Acceptance: 1 May 2014
Last Modified: 04 Jun 2019 15:42
URI: http://orca.cf.ac.uk/id/eprint/100658

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