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. Low-dose 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.