Abstract 16419: Deletion of Low-Density Lipoprotein Receptor in Rats Induces Hyperlipidemia and Atherosclerotic Lesion Formation
The LDL-receptor (LDLR) plays a major role in removing circulating LDL. Deletion of the receptor in mice results in profound dyslipidemia and atherosclerotic lesion formation. Although LDL-R null mice have been used to study atherogenesis, there are significant differences between murine and human atherosclerotic lesion formation and newer animal models of atherosclerosis are urgently needed. We established a new LDLR- null rat model of atherosclerosis. The LDL-null rats were phenotypically normal. However, when maintained on normal chow, the LDLR-null rats had 1.3-fold higher body weight (P<0.01), 3-fold higher plasma cholesterol (P<0.01) and 1.4-fold higher plasma triglyceride (P<0.01) levels at 12 weeks of age when compared with wild-type (WT) rats. When placed on a high fat (HF) diet (42 % fat) for 6-32 weeks, these rats had a 3-5-fold higher levels of plasma cholesterol and triglycerides (P<0.01) than WT rats. NMR analysis of plasma lipoproteins in LDLR-null rats maintained on HF diet for 32 weeks showed lower VLDL (40%; P<0.01) and HDL (20%; P<0.01) particle size, in comparison with WT. Abundance of VLDL particles was increased by 4-fold (P<0.01) and HDL particles by 18-fold (P<0.01) in the HF-fed LDLR-null rats. No lesions were detected in the aortic valve or the aorta of LDLR-null rats after 16 weeks of HF-feeding. However, after 34 weeks of HF diet, appreciable lipid-rich lesions were detected in innominate artery, carotid artery, aortic arch, thoracic and abdominal aorta. Only sparse lesions were detected in the aortic valves. No lesions were detected in LDLR-null rats maintained on NC or the corresponding WT rats maintained on NC or HF-diet. These data suggest that LDLR-null rats are hyperlipidemic and obese, and on high-fat diet, develop diffused atherosclerotic lesions. These studies establish a unique animal model of atherosclerosis that has multiple features resembling atherosclerosis in humans.
- © 2012 by American Heart Association, Inc.