Objective-The role of cholesteryl ester transfer protein (CETP) in the development of atherosclerosis is still undergoing debate. Therefore, we evaluated the effect of human CETP expression on atherosclerosis in APOE*3-Leiden (E3L) mice with a humanized lipoprotein profile. Methods and Results-E3L mice were crossbred with human CETP transgenic mice. On a chow diet, CETP expression increased plasma total cholesterol (TC) (ϩ43%; PϽ0.05). To evaluate the effects of CETP on the development of atherosclerosis, mice were fed a Western-type diet containing 0.25% cholesterol, leading to 4.3-fold elevated TC levels in both E3L and CETP.E3L mice (PϽ0.01). On both diets, CETP expression shifted the distribution of cholesterol from high-density lipoprotein (HDL) toward very-low-density lipoprotein (VLDL)/low-density lipoprotein (LDL). Moreover, plasma of CETP.E3L mice had reduced capacity (Ϫ39%; PϽ0.05) to induce SR-BI-mediated cholesterol efflux from Fu5AH cells than plasma of E3L mice. After 19 weeks on the Western-type diet, CETP.E3L mice showed a 7.0-fold increased atherosclerotic lesion area in the aortic root compared with E3L mice (PϽ0.0001). Conclusions-CETP expression in E3L mice shifts the distribution of cholesterol from HDL to VLDL/LDL, reduces plasma-mediated SR-BI-dependent cholesterol efflux, and represents a clear pro-atherogenic factor in E3L mice. We anticipate that the CETP.E3L mouse will be a valuable model for the preclinical evaluation of HDL-raising interventions on atherosclerosis development. Key Words: CETP Ⅲ cholesterol efflux Ⅲ hyperlipidemia Ⅲ reverse cholesterol transport Ⅲ transgenic mice C ardiovascular disease (CVD) is the leading cause of death in the Western world and its prevalence is increasing in Eastern Europe and developing countries. 1 The main cause of CVD is atherosclerosis, characterized by the combination of chronic inflammation and/or hyperlipidemia. 1 Both low high-density lipoprotein (HDL) cholesterol plasma levels and high very-low-density lipoprotein (VLDL)/lowdensity lipoprotein (LDL) cholesterol levels are independent risk factors for atherosclerosis development. 2 The ratio of VLDL/LDL to HDL is to a great extent affected by the cholesteryl ester transfer protein (CETP). 3 CETP is a transfer factor that mediates the exchange of cholesteryl esters (CE) and triglycerides (TG) between the apoB-containing lipoproteins (ie, chylomicrons, VLDL, and LDL) and HDL in plasma. 3 As such, CETP may be antiatherogenic by facilitating reverse cholesterol transport (RCT) from peripheral tissues to the liver via the VLDL/LDL pathway. Another potential role of CETP in RCT has recently been supported by the observation that CETP mediates HDL-CE uptake by hepatocytes independently of SR-BI and the LDL receptor (LDLr) in vitro. 4 However, CETP may be pro-atherogenic by enhancing the levels of VLDL/LDL with concomitant reduction of anti-atherogenic HDL levels.Many studies in humans have been performed regarding the association between CETP and lipoprotein levels and the subsequent development ...

Treatment with avasimibe potently lowered plasma cholesterol levels in ApoE*3-Leiden mice and considerably reduced atherosclerotic lesion area in addition to its cholesterol-lowering effect. Because monocyte adherence to the endothelium and lesion severity were also reduced by avasimibe, treatment with avasimibe may result in higher plaque stability and therefore a reduced risk of plaque rupture.

Objective-To evaluate whether low-dose atorvastatin suppresses atherosclerotic lesion progression and inflammation in apolipoprotein E*3 (apoE*3)-Leiden mice beyond its cholesterol-lowering effect. Methods and Results-ApoE*3-Leiden mice were fed a high-cholesterol (HC) diet until mild atherosclerotic lesions had formed. Subsequently, HC diet feeding was continued or mice received HC supplemented with 0.002% (w/w) atorvastatin (HCϩA), resulting in 19% plasma cholesterol lowering, or mice received a low-cholesterol (LC) diet to establish a plasma cholesterol level similar to that achieved in the HCϩA group. HCϩA and LC diet reduced, significantly and to the same extent, lesion progression and complication in the aortic root, as assessed by measuring total atherosclerotic lesion area, lesion severity, and macrophage and smooth muscle cell area. In the aortic arch, HCϩA but not LC blocked lesion progression. HCϩA and LC reduced vascular inflammation (ie, expression of macrophage migration inhibitory factor , plasminogen activator inhibitor-1, matrix metalloproteinase-9), but HCϩA additionally suppressed vascular cell adhesion molecule-1 expression and, in parallel, monocyte adhesion. In contrast, low-dose atorvastatin showed no antiinflammatory action toward hepatic inflammation markers (serum amyloid A, C-reactive protein [CRP]) in apoE*3-Leiden mice and human CRP transgenic mice. Conclusion-Low-dose atorvastatin cholesterol-dependently reduces lesion progression in the aortic root but shows antiinflammatory vascular activity and tends to retard atherogenesis in the aortic arch beyond its cholesterol-lowering effect. Key Words: lipids Ⅲ lipoprotein metabolism Ⅲ growth factors Ⅲ pathophysiology D espite remarkable advances in medical therapeutics and in understanding of its biology, atherosclerosis remains a principal cause of death in the Westernized world. 1 Therefore, there is a clear need for more insight into the mechanisms underlying the atherosclerotic process and its (medical) treatment.Atherosclerosis was previously thought to be a disease primarily involving lipid accumulation in the arterial wall. Current concepts of the disease include involvement of the immune system and chronic inflammation as crucial factors in all stages of the atherosclerotic process: the initiation of endothelial dysfunction, fatty streak formation, and lesion progression and complication. 1 This central role of inflammation and immunity in atherogenesis suggests that antiinflammatory therapies might have a beneficial role in management of the disease. In fact, it is now thought that the statin class of lipid-lowering drugs exerts part of the antiatherosclerotic effect via an antiinflammatory property. 2,3 Conferring these so-called "pleiotropic" activities to statins is mainly based on in vitro studies. 4 By interfering with intracellular signaling pathways, statins can suppress certain inflammatory responses in cultured cells. [2][3][4] However, in most of these studies, statin concentrations are used that are not achieved under ...