Apolipoprotein E deficiency accelerates atherosclerosis development in miniature pigs

Abstract

Miniature pigs have advantages over rodents in modeling atherosclerosis because their cardiovascular system and physiology are similar to that of humans. Apolipoprotein E (ApoE) deficiency has long been implicated in cardiovascular disease in humans. To establish an improved large animal model of familial hypercholesterolemia and atherosclerosis, the clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 system (CRISPR/Cas9) was used to disrupt the <i>ApoE</i> gene in Bama miniature pigs. Biallelic-modified <i>ApoE</i> pigs with in-frame mutations (<i>ApoE^m/m </i> ) and frameshift mutations (<i>ApoE^-/- </i> ) were simultaneously produced. <i>ApoE^-/- </i> pigs exhibited moderately increased plasma cholesterol levels when fed with a regular chow diet, but displayed severe hypercholesterolemia and spontaneously developed human-like atherosclerotic lesions in the aorta and coronary arteries after feeding on a high-fat and high-cholesterol (HFHC) diet for 6 months. Thus, these <i>ApoE^-/- </i> pigs could be valuable large animal models for providing further insight into translational studies of atherosclerosis.