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. 2011 Dec;219(2):455-62.
doi: 10.1016/j.atherosclerosis.2011.08.035. Epub 2011 Aug 26.

The LDLR deficient mouse as a model for aortic calcification and quantification by micro-computed tomography

Zuhier Awan  1 , Maxime Denis, Dana Bailey, Adel Giaid, Annik Prat, David Goltzman, Nabil G Seidah, Jacques Genest
Affiliations

The LDLR deficient mouse as a model for aortic calcification and quantification by micro-computed tomography

Zuhier Awan et al. Atherosclerosis. 2011 Dec.

Abstract

Objective: Patients with familial hypercholesterolemia (FH) due mutations in the low-density lipoprotein receptor (LDLR) suffer premature aortic calcification, an effect that is age- and gene dosage-dependent and cholesterol level independent later in life. To better understand this process, we examined a murine model.

Methods: We compared chow fed Ldlr(-/-) mice to controls at 6, 12 and 18 months and on a Western diet (WD) at 6 months. Additionally, we compared controls to Ldlr(-/-) mice and transgenic mice Tg(Pcsk9) overexpressing PCSK9, which promotes LDLR degradation. Aortas were perfused-fixed, embedded in paraffin, and sections were stained with alizarin red. Micro-computerized tomography (micro-CT) was used to quantify vascular calcification.

Results: Ldlr(-/-) mice develop calcification in the ascending, transverse aorta and neck vessels with a distribution similar to that of human. Calcification was most prominent in 18-month-old Ldlr(-/-) mice fed a chow diet and in 6-month-old Ldlr(-/-) mice fed a WD. Interestingly, Tg(Pcsk9) mice fed a WD develop aortic calcifications as well. Histology confirmed that the calcification were predominantly sub-intimal. Marked expression of LRP5 and WNT was observed in the Ldlr(-/-) and Tg(Pcsk9) models, but not in age-matched controls.

Conclusions: The two mouse models develop aortic calcification in an age- and diet-dependent manner. Abnormal regulation of the LRP5/Wnt pathway may play a role in the calcification process. Further analysis of these aortic calcification models using this micro-CT imaging technique may provide a better understanding of the link between FH and arterial calcification.

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Comment in

  • Animal models of vascular calcification.
    Ivanovski O, Nikolov IG. Ivanovski O, et al. Atherosclerosis. 2012 Jun;222(2):574-5; author reply 576. doi: 10.1016/j.atherosclerosis.2011.12.037. Epub 2011 Dec 29. Atherosclerosis. 2012. PMID: 22244767 No abstract available.

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