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Inhibition of Interleukin-1β by a Monoclonal Antibody Therapy Reduces Vascular Calcification in Ldlr-/- Mice

Awan, Zuhier and Denis, Maxime and Awan, Amani and Gram, Hermann and Seidah, Nabil and Genest, Jaques (2015) Inhibition of Interleukin-1β by a Monoclonal Antibody Therapy Reduces Vascular Calcification in Ldlr-/- Mice. Angiology.

Abstract

BACKGROUND: Patients with familial hypercholesterolemia (FH) develop extensive aortic calcification and calcific aortic stenosis. While statins delay this process, LDL-cholesterol lowering alone is not enough to avert it. Recently aortic calcification was reproduced in two animal models, LDL-receptor-deficient (Ldlr-/-) and LDL-receptor-attenuated Tg(Pcsk9) mice. We hypothesized that vascular inflammation initiated by hypercholesterolemia is followed by unchecked mineralization at sites of atherosclerotic plaques and given the link between cholesterol and activation of inflammation via interleukin-1β we thus test the effects of IL-1β inhibition on vascular calcification.
METHODS: A mouse monoclonal antibody (mAB) against IL-1β or (saline) placebo was administered subcutaneously to Ldlr-/- and Tg(Pcsk9) mice (n=58) fed a Western diet. Anthropometric, lipid and glucose profiles were determined. PCSK9, SAA-1 and cytokine expression were measured by ELISA. Aortic calcification was determined by micro-CT and x-ray densitometry while aortic flow velocity was assessed by ultrasound.
RESULTS: Circulating levels of IL-1β in Ldlr-/- mice were twice that observed in Tg(Pcsk9) mice. Anti-IL-1β mAb-treated and placebo-treated mice did not differ in their growth characteristics, lipid or glucose profiles in both models, while mAb-treated mice had lower SAA1 levels. Aortic calcifications was markedly attenuated by anti-IL-1β mAb in Ldlr-/- (a significant reduction 75% by X-ray and 96.3% by micro-CT) than seen with Tg(Pcsk9) mice. However aortic flow velocities were unchanged in both models.
CONCLUSIONS: Herein we demonstrated that aortic calcifications can be inhibited by anti-IL-1β mAb in the LDL-receptor deficient mice. These results have a translational application by preventing vascular calcification in human.

Item Type: Article
Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13
URI: https://oak.novartis.com/id/eprint/10946

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