The Effects of Cholesteryl Ester Transfer Protein Inhibition on High Density Lipoprotein Function

Abstract

Cardiovascular disease affects about 1.4 million Australians and was responsible for more than 45000 deaths in 2011. Compelling evidence from human population studies has shown a positive correlation between elevated plasma high density lipoprotein cholesterol (HDL-C) levels and a reduced risk of major cardiovascular events. HDLs have several potential cardioprotective functions, the most extensively studied of which is their ability to remove excess cholesterol from macrophages. They also have anti-inflammatory properties, enhance endothelial repair and improve endothelial function. HDLs also have anti-oxidant, anti-apoptotic, anti-thrombotic and anti-diabetic functions. Therapies that increase HDL-C levels reduce atherosclerotic lesion development in animals. These observations have led to the hypothesis that increasing HDL-C levels will reduce cardiovascular events in humans. Although CETP inhibitors have been shown to markedly increase HDL-C levels and reduce major cardiovascular events in a recent clinical outcome trial, there remains doubt about the effects of CETP inhibition on the cardioprotective properties of HDLs. The work in this thesis examines the effects of inhibiting CETP on the cardioprotective functions of HDLs. The studies investigate the effects of a novel CETP inhibitor, AMG-899, on HDL composition, size and several of their cardioprotective properties. Subjects were treated with placebo or AMG-899 (2.5 mg/day or 10 mg/day) over 12 weeks. HDLs were isolated from subjects before and after treatment. AMG-899 treatment increased plasma HDL-C levels and decreased LDL-C levels (Chapter 3). Treatment with AMG-899 also changed the composition of HDLs, increased HDL size (Chapter 3) and increased HDL-mediated ABCA1- and ABCG1-specific cholesterol efflux (Chapter 4). Treatment with 10 mg/day AMG-899 also improved the anti-inflammatory properties of HDLs (Chapter 5), while HDLs isolated from subjects after treatment with 2.5 mg/day and 10 mg/day AMG-899 were equally effective at increasing endothelial proliferation and migration relative to HDLs isolated prior to treatment (Chapter 6). These studies establish that inhibiting CETP activity with AMG-899 does not impair, and in some cases, improves the potentially cardioprotective functions of HDLs. In conclusion, as AMG-899 treatment increases HDL-C levels more effectively than other CETP inhibitors, and does not impair the major cardioprotective functions of HDLs, it is a potential candidate for future clinical development.