Apolipoprotein A -I inhibits atherosclerosis in vivo by promoting macrophage reverse cholesterol transport and HDL anti -inflammatory and anti-oxidant functions

Although it is well established that HDL is anti-atherogenic, the mechanisms by which it inhibits atherosclerosis in vivo have not been definitively proven. The goals of this thesis are fourfold: First, to test the hypothesis that apolipoprotein A-I (apoA-I), the primary protein component of HDL, is directly anti-atherogenic. Second, to determine the in vivo relevance of mechanisms by which apoA-I is presumed to inhibit the development of atherosclerosis. In vitro studies have suggested that apoA-I may promote reverse cholesterol transport, inhibit oxidation, and inhibit inflammation, however the role of apoA-I in these processes in vivo has not been clearly established. Third, to gain a better understanding of HDL anti-atherogenic function, with a particular emphasis on understanding the relationship between apoA-I and HDL function. Lastly, to identify novel mechanisms by which apoA-I may function to inhibit the development of atherosclerosis. In order to pursue these goals we established atherosclerosis-susceptible mouse models of apoA-I deficiency as well as models of transgenic expression and overexpression of human apoA-I. Using these models we determined how apoA-I genotype effected the development of atherosclerosis. In addition we determined how apoA-I genotype influenced the reverse cholesterol transport pathway and HDL anti-oxidant and anti-inflammatory function. To identify novel mechanisms by which apoA-I and HDL function to inhibit the development of atherosclerosis we used both the animal models as well as in vitro studies. Our results indicate that apoA-I is directly anti-atherogenic in vivo, independent of the level of HDL cholesterol. Furthermore, apoA-I is required for efficient reverse cholesterol transport as well as for HDL anti-oxidant and anti-inflammatory functions in vivo. We offer a new connection between the lipid-transporting and anti-oxidant and anti-inflammatory functions of apoA-I by demonstrating that apoA-I is an efficient acceptor of ABCA1-mediated oxidized phospholipid efflux from macrophage cells. In conclusion, apoA-I is directly anti-atherogenic by promotion of macrophage reverse cholesterol transport and HDL antioxidant and anti-inflammatory functions. Strategies to augment the level or functional capacity of apoA-I may represent effective options in the prevention and treatment of cardiovascular disease