Atherosclerosis in aged mice over-expressing the reverse cholesterol transport genes

Abstract

We determined whether over-expression of one of the three genes involved in reverse cholesterol transport, apolipoprotein (apo) AI, lecithin-cholesterol acyl transferase (LCAT) and cholesteryl ester transfer protein (CETP), or of their combinations influenced the development of diet-induced atherosclerosis. Eight genotypic groups of mice were studied (AI, LCAT, CETP, LCAT/AI, CETP/AI, LCAT/ CETP, LCAT/AI/CETP, and non-transgenic) after four months on an atherogenic diet. The extent of atherosclerosis was assessed by morphometric analysis of lipid-stained areas in the aortic roots. The relative influence (R 2 ) of genotype, sex, total cholesterol, and its main sub-fraction levels on atherosclerotic lesion size was determined by multiple linear regression analysis. Whereas apo AI (R 2 = 0.22, P < 0.001) and CETP (R 2 = 0.13, P < 0.01) expression reduced lesion size, the LCAT (R 2 = 0.16, P < 0.005) and LCAT/AI (R 2 = 0.13, P < 0.003) genotypes had the opposite effect. Logistic regression analysis revealed that the risk of developing atherosclerotic lesions greater than the 50th percentile was 4.3-fold lower for the apo AI transgenic mice than for non-transgenic mice, and was 3.0-fold lower for male than for female mice. These results show that apo AI overexpression decreased the risk of developing large atherosclerotic lesions but was not sufficient to reduce the atherogenic effect of LCAT when both transgenes were co-expressed. On the other hand, CETP expression was sufficient to eliminate the deleterious effect of LCAT and LCAT/AI overexpression. Therefore, increasing each step of the reverse cholesterol transport per se does not necessarily imply protection against atherosclerosis while CETP expression can change specific atherogenic scenarios.

Lecithin:cholesterol acyltransferase: old friend or foe in atherosclerosis?

“…As mice are naturally resistant to atherosclerosis, the average lesion size in the animals was small, with a maximum lesion size of ‫ف‬ 25,000 m 2 in the human LCAT transgenic mice with 240 copies of the transgene. In the Francone mice ob the FVB background, a ‫ف‬ 2.5-fold nonsignifi cant increase in lesion size was observed ( 119 ). In the presence of human apoAI, however, a signifi cant 3.4-fold increase in lesion size was found.…”

“…Furthermore, it has to be taken into account that cholate-containing diets can have detrimental effects on liver function. For example, in the study of Berti and colleagues using the Francone human LCAT transgenic mice, it was clearly stated that 19% of the mice died during the 16-week dietfeeding period and that at the end of the study, all mice showed signals of hepatic steatosis and had gall bladders full of gallstones ( 119 ).…”

Molecular Biology of Atherosclerosis

“…Atherosclerosis extent was strongly and directly proportional to the ratio (LDL-C ϩ VLDL-C)/HDL-C. In the setting of human LCAT over-expression, CETP actually decreased atherosclerosis (137). Thus, relevance to human is unclear.…”

Cholesteryl ester transfer protein: The controversial relation to atherosclerosis and emerging new biological roles

“…Several studies using CETP transgenic models showed that CETP expression could be either pro-or anti-atherogenic. CETP expression plays a protective role in conditions such as hypertriglyceridemia (20), overexpression of LCAT (21,22), excess of apo B combined with lipoprotein lipase deficiency and diabetes (23), diabetes and obesity (24), castration (25,26), and SRBI deficiency (27). Conversely, CETP exacerbates atherosclerosis when expressed in very high levels (seven-fold simian plasma levels) (28), in severe hypercholesterolemia due to the deletion of LDL receptors or apo E genes (29) and in hypertensive rats (30).…”

“…This role of CETP seems to be relevant since CETP deficient patients have higher levels of oxLDL (56). In addition, ovariectomized CETP transgenic mice present levels of anti-oxLDL antibodies that are lower than their CETP non-expressing littermates (22). Protection against lipoprotein oxidation is a well-known anti-atherogenic action of estrogen (57).…”