title: The LDLR deficient mouse as a model for aortic calcification and quantification by micro-computed tomography.
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.
authors: Institut de Recherches Cliniques, Montreal, Quebec, Canada.
authors: Zuhier
authors: Z
authors: Awan
authors: Maxime
authors: M
authors: Denis
authors: Dana
authors: D
authors: Bailey
authors: Adel
authors: A
authors: Giaid
authors: Annik
authors: A
authors: Prat
authors: David
authors: D
authors: Goltzman
authors: Nabil G
authors: NG
authors: Seidah
authors: Jacques
authors: J
authors: Genest
mesh_terms: D000367:Age Factors; D000375:Aging; D000818:Animals; D001018:Aortic Diseases / Q000000981:diagnostic imaging* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001027:Aortography / Q000379:methods*; D015415:Biomarkers / Q000097:blood; D002784:Cholesterol / Q000097:blood; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D018450:Disease Progression; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016612:Paraffin Embedding; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D012720:Severity of Illness Index; D013194:Staining and Labeling; D061205:Vascular Calcification / Q000000981:diagnostic imaging* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051153:Wnt Proteins / Q000378:metabolism; D055114:X-Ray Microtomography
chemical_list: D015415:Biomarkers; D060492:Low Density Lipoprotein Receptor-Related Protein-5; C555483:Lrp5 protein, mouse; D011973:Receptors, LDL; D051153:Wnt Proteins; D002784:Cholesterol; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases