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

• Published in: Atherosclerosis 2011-12, Vol.219 (2), p.455-462
• Main Authors: Awan, Zuhier, Denis, Maxime, Bailey, Dana, Giaid, Adel, Prat, Annik, Goltzman, David, Seidah, Nabil G, Genest, Jacques
• Format: Article
• Language: English
• Subjects: Age Factors; Aging; alizarin; animal models; Animals; aorta; Aortic calcification and micro-computed tomography; Aortic Diseases - diagnostic imaging; Aortic Diseases - genetics; Aortic Diseases - metabolism; Aortic Diseases - pathology; Aortography - methods; atherosclerosis; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Biomarkers - blood; Blood and lymphatic vessels; calcification; Cardiology. Vascular system; Cardiovascular; cholesterol; Cholesterol - blood; Diet, High-Fat; Disease Models, Animal; Disease Progression; Diseases of the aorta; Familial hypercholesterolemia; gene overexpression; genes; genetically modified organisms; histology; humans; hypercholesterolemia; image analysis; LDLR; low density lipoprotein; Low Density Lipoprotein Receptor-Related Protein-5 - metabolism; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; micro-computed tomography; mutation; neck; Paraffin Embedding; patients; PCSK9; Proprotein Convertase 9; Proprotein Convertases; Receptors, LDL - deficiency; Receptors, LDL - genetics; Serine Endopeptidases - genetics; Serine Endopeptidases - metabolism; Severity of Illness Index; Staining and Labeling; Vascular Calcification - diagnostic imaging; Vascular Calcification - genetics; Vascular Calcification - metabolism; Vascular Calcification - pathology; Western diets; Wnt Proteins - metabolism; X-Ray Microtomography
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2011.08.035

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.