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    ABSTRACT: Cholesteryl ester transfer protein (CETP) is a plasma protein that mediates the exchange of cholesteryl ester in high-density lipoprotein (HDL) for triglyceride in very low density lipoprotein (VLDL). This process decreases the level of anti-atherogenic HDL cholesterol and increases pro-atherogenic VLDL and low density lipoprotein (LDL) cholesterol, so CETP is potentially atherogenic. On the other hand, CETP could also be anti-atherogenic, because it participates in reverse cholesterol transport (transfer of cholesterol from peripheral cells through the plasma to the liver). Because the role of CETP in atherosclerosis remains unclear, we have attempted to develop a potent and specific CETP inhibitor. Here we describe CETP inhibitors that form a disulphide bond with CETP, and present one such inhibitor (JTT-705) that increases HDL cholesterol, decreases non-HDL cholesterol and inhibits the progression of atherosclerosis in rabbits. Our findings indicate that CETP may be atherogenic in vivo and that JTT-705 may be a potential anti-atherogenic drug.
    Nature 01/2000; · 38.60 Impact Factor
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    ABSTRACT: Although numerous studies have investigated the relationship between cholesteryl ester transfer protein (CETP) and high density lipoprotein (HDL) remodeling, the relationship between CETP and low density lipoproteins (LDL) is still not fully understood. In the present study, we examined the effect of the inhibition of CETP on both LDL oxidation and the uptake of the oxidized LDL, which were made from LDL under condition of CETP inhibition, by macrophages using a monoclonal antibody (mAb) to CETP in incubated plasma. The 6-h incubation of plasma derived from healthy, fasting human subjects led to the transfer of cholesteryl ester (CE) from HDL to VLDL and LDL, and of triglycerides (TG) from VLDL to HDL and LDL. These net mass transfers of neutral lipids among the lipoproteins were eliminated by the mAb. The incubation of plasma either with or without the mAb did not affect the phospholipid compositions in any lipoproteins. As a result, the LDL fractionated from the plasma incubated with the mAb contained significantly less CE and TG in comparison to the LDL fractionated from the plasma incubated without the mAb. The percentage of fatty acid composition of LDL did not differ among the unincubated plasma, the plasma incubated with the mAb, and that incubated without the mAb. When LDL were oxidized with CuSO4, the LDL fractionated from the plasma incubated with the mAb were significantly resistant to the oxidative modification determined by measuring the amount of TBARS and by continuously monitoring the formation of the conjugated dienes, in comparison to the LDL fractionated from the plasma incubated without the mAb. The accumulation of cholesteryl ester of oxidized LDL, which had been oxidized for 2 h with CuSO4, in J774.1 cells also decreased significantly in the LDL fractionated from the plasma incubated with mAb in comparison to the LDL fractionated from the plasma incubated without the mAb. These results indicate that CETP inhibition reduces the composition of CE and TG in LDL and makes the LDL resistant to oxidation. In addition, the uptake of the oxidized LDL, which was made from the LDL under condition of CETP inhibition, by macrophages also decreased.
    The Journal of Lipid Research 02/2000; 41(1):126-33. · 4.39 Impact Factor
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    ABSTRACT: Atherosclerosis in venous coronary artery bypass grafts begins early and accelerates from the fifth post-operative year. We studied the influence of 18 variables existing at the time of operation, and of 'classical' risk factors present at 1 and 5 years after operation on the long-term outcome of this type of surgery. Four hundred twenty-eight consecutive patients who underwent isolated venous coronary bypass surgery between April 1, 1976 and April 1, 1977 were followed prospectively. Follow-up was 99.3% complete with a mean duration of 22.8 years for the survivors. Multivariate analysis was performed using the Cox regression model. Actuarial survival after 5, 10, 15 and 20 years is 95, 83, 63 and 47%, respectively. The cumulative probability of event-free survival for cardiac death, acute myocardial infarction and re-intervention at 5, 10, 15 and 20 years, respectively, are 98, 90, 74, 60%; 99, 91, 83, 77%; and 97, 86, 67, 57%. Age and left ventricular functions are continuous incremental risk factors for mortality. Left ventricular function and completeness of revascularization, and age and vessel disease are independent predictors of cardiac death and re-intervention, respectively. Hypertension, diabetes mellitus, hypertriglyceridemia, obesity and smoking, present after operation have an independent influence on the occurrence of cardiac events. Risk factors (still) existing 1 and 5 years after operation have a negative influence on the long-term results. This emphasizes the need of treatment of these 'classical' risk factors still present after operation.
    European Heart Journal 06/2003; 24(10):927-36. · 14.10 Impact Factor

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