Abstract 14053: Development of Hypercholesterolemia-Induced Complex Unstable Atherosclerotic Lesions in a Novel Low Density Lipoprotein Receptor Knockout Pig
Background: Atherosclerotic plaque rupture is the most common cause of acute coronary syndrome, but the detail process of plaque development and rupture is not well known by lack of suitable animal models. Because of similarities to human coronary size, pathoanatomy, and physiology, swine is an ideal animal model for the study of human coronary artery disease. Here we generated low density lipoprotein receptor (LDLR) knockout pigs, which developed hypercholesterolemia-induced atherosclerosis.
Methods and Results: LDLR exon regions were targeted deleted in cultured porcine fetal fibroblasts. LDLR knockout clone embryos were generated by microinjection of nuclei of fetal fibroblasts into enucleated oocytes. Plasma concentration of LDL cholesterol was 2 fold greater in F1 heterozygous LDLR knockout (LDLR+/-) pigs, and 14 fold greater in F2 homozygous LDLR knockout (LDLR-/-) pigs than that in wild type (WT) littermates (WT: 35±4, LDLR+/-: 71±9, LDLR-/-: 501±34 mg/dl). With chow diet, by 6 month of age, compared to WT and LDLR+/- pigs, LDLR-/- pigs developed atherosclerotic lesions in aorta, carotid, femoral, and coronary arteries that were composed of foam cells, inflammatory cells, and smooth muscle cells. Coronary lesions also exhibited calcium deposits and micro mural thrombus. When 3-month-old LDLR-/- pigs were fed with 1.5% cholesterol, 15% fat diet for another 4 months, complicated stenotic plaque containing necrotic core with fibrous caps, cholesterol clefts, calcium deposits, neovascularization, plaque hemorrhage, media rupture, and adventitia inflammatory reaction were exhibited in the coronary lesions, which indicates a high risk for unstable plaque rupture. Intravascular ultrasound (IVUS) observation revealed coronary artery plaques with positive remodeling. Long-term continuous observation of plaque development by angiography, IVUS, angioscopy, and optical coherence tomography is in process.
Conclusions: LDLR-/- pigs develop complicated atherosclerotic plaque which is similar to human unstable atherosclerotic lesions and can be used as a novel atherosclerosis animal model for investigation of the mechanism of unstable plaque rupture and percutaneous intervention therapy.
- © 2012 by American Heart Association, Inc.