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

Petya Valcheva, Anna Cardus, Sara Panizo, Eva Parisi, Milica Bozic, Jose M. Lopez Novoa, Adriana Dusso, Elvira Fernández, Jose M. Valdivielso

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

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 invitro 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. Invivo 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.

Original languageEnglish
Pages (from-to)247-255
Number of pages9
JournalAtherosclerosis
Volume235
Issue number2
DOIs
StatePublished - Aug 2014

Keywords

  • Angiotensin-II
  • ROS
  • Senescence
  • VSMC
  • Vitamin D

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