Overexpression of Cholesteryl Ester Transfer Protein Increases Macrophage-Derived Foam Cell Accumulation in Atherosclerotic Lesions of Transgenic Rabbits

Abstract

High levels of plasma high-density lipoprotein-cholesterol (HDL-C) are inversely associated with the risk of atherosclerosis and other cardiovascular diseases; thus, pharmacological inhibition of cholesteryl ester transfer protein (CETP) is considered to be a therapeutic method of raising HDL-C levels. However, many CETP inhibitors have failed to achieve a clinical benefit despite raising HDL-C. In the study, we generated transgenic (Tg) rabbits that overexpressed the human CETP gene to examine the influence of CETP on the development of atherosclerosis. Both Tg rabbits and their non-Tg littermates were fed a high cholesterol diet for 16 weeks. Plasma lipids and body weight were measured every 4 weeks. Gross lesion areas of the aortic atherosclerosis along with lesional cellular components were quantitatively analyzed. Overexpression of human CETP did not significantly alter the gross atherosclerotic lesion area, but the number of macrophages in lesions was significantly increased. Overexpression of human CETP did not change the plasma levels of total cholesterol or low-density lipoprotein cholesterol but lowered plasma HDL-C and increased triglycerides. These data revealed that human CETP may play an important role in the development of atherosclerosis mainly by decreasing HDL-C levels and increasing the accumulation of macrophage-derived foam cells.

The lipid transfer properties of CETP define the concentration and composition of plasma lipoproteins

“…For example, many studies have examined the effect of CETP expression in species that do not naturally express this protein, including mice [for example, (40)(41)(42)(43)], rats (44)(45)(46), and pigs (47). One study reported the expression of human CETP in rabbits, a species where CETP is native (48). In these cholesterol-fed rabbits, a 2-fold increase in plasma CETP mass reduced HDL cholesterol by 30%, but it did not change plasma TC or LDL cholesterol or alter atherosclerotic lesion size.…”

Genetically Modified Rabbits for Cardiovascular Research

“…This direct relationship between amino acid sequence and DNA recognition has made engineering sequence specific binding domains much easier than ZFNs (Boch et al, 2009;Moscou and Bogdanove, 2009). Using TALEN technology, Lai's laboratory at GIBH, immediately generated two kinds of KO rabbits: an immunodeficent KO rabbit with deficiency of Rag1 and Rag2 genes (Song et al, 2013) and fumarylacetoacetate hydrolase deficient rabbits (Li et al, 2017), which mimics human genetic disease tyrosinemia type I, an autosomal recessive disorder caused by mutations in the both copies of the gene encoding the enzyme. Although TALENs are considered superior to ZFNs in terms of fewer off-target effects, easy design and production, it was soon replaced by the CRISPR-Cas9 based genome editing technology, which is even more rapid and modular than the TALEN platform.…”

Gender specific effect of CETP rs708272 polymorphism on lipid and atherogenic index of plasma levels but not on the risk of coronary artery disease

“…[10] Overexpression of CETP might contribute to the development of atherosclerosis by decreasing serum HDL-C levels and increasing the accumulation of macrophage-derived foam cells in lesions. [11] In addition, baseline CETP levels might predict the lipid-reducing effects of statin. [12] CETP inhibitors could increase the serum HDL-C levels and reduce the incidence of diabetes.…”