This model features targeted disruption of the endogenous LDLR (low-density lipoprotein receptor) gene.
In humans, loss-of-function mutations in LDLR lead to familial hypercholesterolemia, characterized by elevated plasma concentrations of cholesterol. Heterozygotes exhibit higher cholesterol levels and an increased risk for atherosclerosis.
Benefits of the Model:
Consistent, stable hypercholesterolemia that can be further modulated by diet
Predictable, progressive atherosclerosis that manifests on an accelerated timeline
Atherosclerotic lesion formation in the aorta and coronary arteries that model key pathophysiological aspects of human atherosclerosis
Defined Yucatan miniature swine genetics that offer greater consistency, smaller size, and lower cost to house and manage
ExeGen® heterozygote (LDLR+/-) MiniSwine are healthy at birth, with cholesterol levels similar to wild-type controls (LDLR+/+) when fed a normal diet (ND). However, when both groups are fed a Western-style diet (WD) for 25 weeks, the heterozygotes develop consistent, stable hypercholesterolemia, with significantly higher total cholesterol levels (>500 mg/dl) than in the control group. Like in humans, these levels are reduced when given a daily statin dose.
The Western-style diet was formulated to be more representative of human consumption containing natural sources of saturated fat and cholesterol.
Figure 1. Total Cholesterol Levels in LDLR+/- and LDLR+/+ MiniSwine on Normal and Western-Style Diets
ExeGen® LDLR+/- MiniSwine fed a Western-style diet develop atherosclerotic lesions on an accelerated timeline.
Figure 2. Atherosclerotic lesions in the aorta of an 11 month old ExeGen® LDLR+/- MiniSwine fed a western-style diet for 6 months.
A. H&E staining of cross section; luminal side is at the top.
B. Magnification of insidicates area from A shows an plaque with possible proliferating smooth muscles cells.
Figure 3. Atherosclerotic lesions in the coronary arteries of an 11 month old ExeGen® LDLR+/- MiniSwine fed a western-style diet for 6 months.
A. H&E staining of the anterior descending artery shows an early plaque
B. Magnification of indicated region in A shows possible calcification.