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

Area of Science:

• Cardiovascular Biology
• Genetics
• Metabolic Diseases

Background:

• Familial hypercholesterolemia (FH) patients with low-density lipoprotein receptor (LDLR) mutations experience premature aortic calcification.
• This calcification is age- and gene dosage-dependent and cholesterol-independent later in life.

Purpose of the Study:

• To investigate aortic calcification in murine models of FH.
• To understand the role of LDLR deficiency and PCSK9 overexpression in vascular calcification.

Main Methods:

• Comparison of chow-fed Ldlr(-/-) mice with controls at 6, 12, and 18 months.
• Assessment of mice on a Western diet (WD) at 6 months.
• Evaluation of transgenic mice overexpressing PCSK9 (Tg(Pcsk9)) on a WD.
• Quantification of aortic calcification using micro-computerized tomography (micro-CT) and alizarin red staining.

Main Results:

• Ldlr(-/-) mice exhibited aortic calcification in patterns similar to humans.
• Calcification was most severe in older Ldlr(-/-) mice on chow and younger Ldlr(-/-) mice on WD.
• Tg(Pcsk9) mice on WD also developed aortic calcifications.
• Histology revealed predominantly sub-intimal calcification with marked LRP5 and WNT pathway expression in affected mice.

Conclusions:

• Murine models demonstrate age- and diet-dependent aortic calcification.
• The LRP5/Wnt pathway may be implicated in FH-related arterial calcification.
• Micro-CT imaging of these models aids understanding of FH and arterial calcification links.