Valcheva Petya, Cardus Anna, Panizo Sara, Parisi Eva, Bozic Milica, Lopez Novoa Jose M, Dusso Adriana, Fernández Elvira, Valdivielso Jose M
Experimental Nephrology Laboratory, Department of Experimental Medicine, Biomedical Research Institute of Lleida (IRBLLEIDA), Lleida, Spain.
Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain.
Atherosclerosis. 2014 Aug;235(2):247-55. doi: 10.1016/j.atherosclerosis.2014.05.911. Epub 2014 May 13.
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.
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 p57(Kip2). The in vitro findings were confirmed histologically in aortas from wild-type and VDRKO mice.
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 p57(Kip2), 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 p57(Kip2) in aortas from VDRKO mice.
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.
维生素D的活性形式对肾素 - 血管紧张素系统的抑制作用有助于维持正常维生素D水平对心血管健康的益处。血管壁中血管紧张素 - II的局部产生是氧化应激的强效介质，可促使细胞过早衰老。在此，我们的目的是研究维生素D信号缺陷对局部血管紧张素 - II水平和动脉健康的影响。
使用来自野生型和维生素D受体基因敲除（VDRKO）小鼠的主动脉血管平滑肌细胞（VSMC）原代培养物来评估细胞生长、血管紧张素 - II和超氧阴离子的产生以及组织蛋白酶D、血管紧张素 - II 1型受体和p57（Kip2）的表达水平。体外研究结果在野生型和VDRKO小鼠的主动脉中得到了组织学证实。
与野生型小鼠相比，VDRKO小鼠的VSMC在培养物中产生更多的血管紧张素 - II，并引发更高水平的组织蛋白酶D（一种具有肾素样活性的酶）和血管紧张素 - II 1型受体。因此，VDRKO VSMC表现出更高的细胞内超氧阴离子产生，这可被组织蛋白酶D、血管紧张素 - II 1型受体或NADPH氧化酶拮抗剂抑制。VDRKO细胞呈现出更高水平的p57（Kip2）、增殖受损和过早衰老，在抑制血管紧张素 - II信号传导后，所有这些情况均得到缓解。体内研究证实VDRKO小鼠主动脉中组织蛋白酶D、血管紧张素 - II 1型受体和p57（Kip2）水平更高。
活性维生素D对血管健康的有益作用可能是由于局部血管紧张素 - II和下游自由基产生减少，从而防止了VSMC的过早衰老。
