Abstract
BackgroundMice deficient in the LDL receptor (Ldlr −/− mice) have been widely used as a model to mimic human atherosclerosis. However, the time-course of atherosclerotic lesion development and distribution of lesions at specific time-points are yet to be established. The current study sought to determine the progression and distribution of lesions in Ldlr −/− mice.Methodology/Principal FindingsLdlr-deficient mice fed regular chow or a high-fat (HF) diet for 0.5 to 12 months were analyzed for atherosclerotic lesions with en face and cross-sectional imaging. Mice displayed significant individual differences in lesion development when fed a chow diet, whereas those on a HF diet developed lesions in a time-dependent and site-selective manner. Specifically, mice subjected to the HF diet showed slight atherosclerotic lesions distributed exclusively in the aortic roots or innominate artery before 3 months. Lesions extended to the thoracic aorta at 6 months and abdominal aorta at 9 months. Cross-sectional analysis revealed the presence of advanced lesions in the aortic sinus after 3 months in the group on the HF diet and in the innominate artery at 6 to 9 months. The HF diet additionally resulted in increased total cholesterol, LDL, glucose, and HBA1c levels, along with the complication of obesity.Conclusions/SignificanceLdlr-deficient mice on the HF diet tend to develop site-selective and size-specific atherosclerotic lesions over time. The current study should provide information on diet induction or drug intervention times and facilitate estimation of the appropriate locations of atherosclerotic lesions in Ldlr −/− mice.
Highlights
Numerous efforts have been made to determine the pathogenesis and optimal treatments for atherosclerosis, which, together with related complications, presents the leading cause of death in industrialized countries
Apoe-deficient mice have been extensively investigated with regard to diet, lipoprotein metabolism, and the atherosclerotic lesion progression process [4,5], resulting in their wide usage as models to mimic human atherosclerosis
We have documented the time-course of hyperlipidemia, hyperglycemia, obesity, and most importantly, atherosclerotic lesions with anatomic location selectivity and diverse sizes, induced by a high-fat diet in Ldlr2/2 mice
Summary
Numerous efforts have been made to determine the pathogenesis and optimal treatments for atherosclerosis, which, together with related complications, presents the leading cause of death in industrialized countries. Apoe-deficient mice have been extensively investigated with regard to diet, lipoprotein metabolism, and the atherosclerotic lesion progression process [4,5], resulting in their wide usage as models to mimic human atherosclerosis. Previous studies have demonstrated that Ldlr2/2 mice show moderate lipid levels and develop no or only mild atherosclerosis when fed a regular chow diet, in contrast to dramatically elevated cholesterol levels and prominent lesions all over the aorta after 8 months on the Paigen diet [6], supporting their utility as promising models for investigating the pathogenesis of atherosclerosis [7,8,9,10,11,12]. While extensive data have been obtained on lesion development in Apoe2/2 mice, atherosclerotic lesion progression over time and distribution of lesions at specific time-points in Ldlr2/2 mice remain to be defined. The current study sought to determine the progression and distribution of lesions in Ldlr2/2 mice
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