Cholesteryl ester transfer protein expression attenuates atherosclerosis in ovariectomized mice

Abstract

(2); however, the precise effects of CETP on atherogenesis are controversial. In humans, increased incidence of coronary heart disease has been associated with both CETP deficiency (3) and augmentation (4). In several animal models of atherosclerosis, the effects of CETP on vascular health are clearly dependent upon the metabolic context (5-11).Various researchers are attempting to target CETP as a form of therapy (9-13), but these approaches will be useless unless the circumstances where CETP acts as pro-or anti-atherogenic are properly clarified.Deficiency in endogenous estrogen accounts for the loss of protection against coronary heart disease after menopause or following bilateral ovariectomy (14). Estrogen deficiency per se does not alter plasma CETP activity as shown in castrated CETP transgenic mice (15). Also, estrogen therapy has no impact on the plasma CETP activity in humans (16) as well as in apolipoprotein B/CETP double transgenic mouse model (17).The present study aimed at investigating whether CETP expression would alter the development of atherosclerosis in a moderately hypercholesterolemic mouse model lacking ovarian hormones. For this purpose, mice expressing the human CETP gene were crossbred with LDL receptor (LDLR) knockout mice. On a high fat diet, the LDLR knockout mice develop extensive aorta atherosclerosis in a pattern similar to humans (18,19). We have shown here that the expression of the CETP gene significantly reduced the development of atherosclerotic lesions in ovariectomized hypercholesterolemic mice. Furthermore, this antiatherogenic effect of CETP was blunted by the estrogen replacement therapy.

Overexpression of apolipoprotein CIII increases and CETP reverses diet-induced obesity in transgenic mice

“…22,23 In addition, CETP expression stimulates the selective uptake of HDL-derived cholesteryl ester by the liver and other tissues 24 and by human adipocytes 25,26 and protects against atherosclerosis in specific conditions such as hypertriglyceridemia 27 and sexhormone deficiency. 28,29 By reducing HDL cholesterol levels, CETP has been considered a major target for developing inhibitors aimed at reducing atherosclerosis risk (for review see Clark 30 ). However, unexpected negative outcomes from large-scale clinical trial testing the CETP-inhibitor torcetrapib have seriously questioned this strategy.…”

Inhibition of CETP activity by torcetrapib reduces susceptibility to diet-induced atherosclerosis in New Zealand White rabbits

“…Under conditions in which hepatic apoB uptake is downregulated, CETP action results in a CE enrichment of non-HDL lipoproteins, which could contribute to atherogenesis. Perhaps because of these complexities, the introduction of the CETP transgene into mice of various genetic backgrounds has not yielded a consistent effect on athero-sclerosis (12)(13)(14)(15)(16), adding uncertainty to the role of CETP in atherogenesis.…”

High-Density Lipoprotein Inhibits the Uptake of Modified Low- Density Lipoprotein and the Expression of CD36 and FcγRI

“…Our results suggest that the expression of Fc RI is significantly diminished in the presence of HDL in an assay with mLDL. With regard to the role of antibodies in the atherosclerotic process, the present finding suggests that Fc RI inhibition is important in the prevention of atheroma formation because areas of atherosclerotic lesions have been shown to have a positive correlation with the levels of antibodies against oxLDL 49) . However, the roles of antibodies against mLDL are diverse as they can also be protective in the atherosclerotic process depending on their specificity, as shown in other studies 8,50,51) .…”