Low-Dose Calcitriol Decreases Aortic Renin, Blood Pressure, and Atherosclerosis in Apoe-Null Mice

Abstract

Aims:To determine whether low-dose calcitriol attenuates atherosclerosis in apoE-null mice and, if so, through which predominant mechanism. Methods: Starting at the age of 6 weeks, mice received intraperitoneal injections of either 0.25 ng/g body weight of calcitriol or the vehicle, every other day for 8 weeks.Results: Calcitriol treatment resulted in 35% reduction of atherosclerosis at the aortic sinus, and in a significant decrease in blood pressure. These effects were possibly mediated by downregulation of the renin-angiotensin system (RAS), as there was a 64% decrease in the aortic level of renin mRNA. None of the other components of the RAS or the prorenin receptor were affected by treatment. Lowdose calcitriol treatment did not modify the plasma level of monocyte chemoattractant protein-1, interferon γ, interleukin-4 and interleukin-10, which were similar in control and treated mice. Likewise, there was no difference in the percentage of splenic Foxp3 ＋ regulatory T cells. Calcitriol treatment resulted in an unfavorable metabolic profile (glucose and lipids), as determined after a limited fast, a difference that disappeared after food was withheld for a longer time. Conclusions: At a relatively low dosage, calcitriol attenuates the development of atherosclerosis in apoE-null mice, most probably by down regulation of RAS, and not through immunomodulation; however, even at this low dose, calcitriol appears to elevate calcium and to have potentially adverse metabolic effects. Exploring the potential antiatherogenic effects of non-calcemic and safer analogues is therefore warranted.

1,25-Dihydroxyvitamin D3 Causes ADAM10-Dependent Ectodomain Shedding of Tumor Necrosis Factor Receptor 1 in Vascular Smooth Muscle Cells

“…In epidemiologic studies, a link was found between vitamin D deficiency and atherosclerotic cardiovascular disease (Dobnig et al, 2008;Giovannucci et al, 2008). In apolipoprotein E knockout mice, 1,25D 3 administration induced a marked reduction in the formation of atherosclerotic lesions (Takeda et al, 2010;Ish-Shalom et al, 2012). In these studies, 1,25D 3 was shown to prevent the development of atherosclerosis by changing the function or differentiation of dendritic cells and regulatory T cells (Takeda et al, 2010) or by downregulation of the renin-angiotensin system (Ish-Shalom et al, 2012).…”

“…In apolipoprotein E knockout mice, 1,25D 3 administration induced a marked reduction in the formation of atherosclerotic lesions (Takeda et al, 2010;Ish-Shalom et al, 2012). In these studies, 1,25D 3 was shown to prevent the development of atherosclerosis by changing the function or differentiation of dendritic cells and regulatory T cells (Takeda et al, 2010) or by downregulation of the renin-angiotensin system (Ish-Shalom et al, 2012). 1,25D 3 suppresses renin gene expression by blocking the binding of cAMP response element-binding protein to cAMP response element in the promoter of the gene (Yuan et al, 2007) and thereby reduces the production of angiotensin II, a potent proatherogenic peptide.…”

The Proatherogenic Effect of Chronic Nitric Oxide Synthesis Inhibition in ApoE-Null Mice Is Dependent on the Presence of PPARα

“…There were thus 4 experimental groups, each comprising approximately 20 mice. At the age of 8 weeks, noninvasive basal blood pressure was obtained as described [12], and animals were switched to a high fat Western diet (Teklad diet 88317, Harlan, Madison, WI) for 8 weeks. L-NAME administration was continued throughout the experiment.…”

“…Quantification of the plaques was performed using a digital imaging processing program (NIS element Br 3.0 imaging system) (Nikon Instruments Europe B.V., The Netherlands), as described [12]. …”

The Role of the Intraplaque Vitamin D System in Atherogenesis

“…By deleting VDR gene in LDLr − / − mice, Szeto and coworkers firstly suggested that inhibition of macrophage VDR signalling in atherosclerotic mice also suppressed the RAAS [100]. Further studies by Ish-Shalom and colleagues and Weng and coworkers have recently supported these findings in mice [148, 149]. In addition, the discovery of fibroblast growth factor (FGF)23/klotho axis has also broadened the potential role of vitamin D on the endocrine signalling in the pathogenesis of atherosclerosis.…”