Low-dose calcitriol decreases aortic renin, blood pressure, and atherosclerosis in apoe-null mice.
OBJECTIVE
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.
The Institute of Endocrinology, Metabolism and Hypertension, Tel Aviv Sourasky Medical Center, Israel.
Maya
M
Ish-Shalom
Jessica
J
Sack
Michal
M
Vechoropoulos
Aviv
A
Shaish
Michal
M
Entin-Meer
Yehuda
Y
Kamari
Sophia
S
Maysel-Auslender
Gad
G
Keren
Dror
D
Harats
Naftali
N
Stern
Karen
K
Tordjman
D000818:Animals; D001011:Aorta / Q000201:enzymology / Q000378:metabolism*; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000378:metabolism*; D001483:Base Sequence; D001794:Blood Pressure; D002117:Calcitriol / Q000008:administration & dosage*; D016207:Cytokines / Q000097:blood; D017931:DNA Primers; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D051379:Mice; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000378:metabolism; D016133:Polymerase Chain Reaction; D012083:Renin / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology
D001057:Apolipoproteins E; D016207:Cytokines; D017931:DNA Primers; D019255:NADPH Oxidases; D012083:Renin; D002117:Calcitriol