TY - JOUR
T1 - Lack of vitamin D receptor causes stress-induced premature senescence in vascular smooth muscle cells through enhanced local angiotensin-II signals
AU - Valcheva, Petya
AU - Cardus, Anna
AU - Panizo, Sara
AU - Parisi, Eva
AU - Bozic, Milica
AU - Lopez Novoa, Jose M.
AU - Dusso, Adriana
AU - Fernández, Elvira
AU - Valdivielso, Jose M.
N1 - Publisher Copyright:
© 2014 Elsevier Ireland Ltd.
PY - 2014/8
Y1 - 2014/8
N2 - 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.
AB - 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.
KW - Angiotensin-II
KW - ROS
KW - Senescence
KW - VSMC
KW - Vitamin D
UR - http://www.scopus.com/inward/record.url?scp=84907077054&partnerID=8YFLogxK
U2 - 10.1016/j.atherosclerosis.2014.05.911
DO - 10.1016/j.atherosclerosis.2014.05.911
M3 - Article
C2 - 24880896
AN - SCOPUS:84907077054
SN - 0021-9150
VL - 235
SP - 247
EP - 255
JO - Atherosclerosis
JF - Atherosclerosis
IS - 2
ER -