High density lipoprotein (HDL) plays a critical role in preventing CVD. Inflammation is ofcentral importance in the pathogenesis of atherosclerosis. Chronic inflammation leads to changesin HDL [e.g. decreased apolipoprotein A-l (apo A-l) and paraoxonase (PON1), and increased SAAand other novel proteins identified by mass spectrometry]. These changes are associated with aloss of its atheroprotective properties. Inflammation also may lead to pro-atherogenic changes inHDL. We hypothesize that compositional and functional changes in HDL induced by inflammationprovides an important link between inflammation and atherosclerosis. We also hypothesize thatchanges in HDL composition may be biomarkers that indicate the presence of oxidative damageand/or atherosclerosis at the level of the artery wall. To test these hypotheses, we plan todetermine how inflammation (acute and chronic) influences HDL composition, function and role inatherogenesis in mice. Next, we will test the mechanism by which inflammation reduces theatheroprotective HDL apolipoproteins apo A-l and PON1, and increases the potentially proatherogenicapolipoprotein SAA in HDL. Third, we will determine whether local over-expression bymacrophages of inflammatory and anti-inflammatory proteins present in HDL affects the initiationand/or progression of atherosclerosis in a mouse model of hypercholesterolemia. Finally, we willdetermine whether chronic inflammation alters the composition and functional properties of HDL inhumans in a manner similar to that in mice, and whether changes in HDL protein composition aremarkers of oxidation and/or atherosclerosis Many of these studies will involve the use of novelmass spectrometric approaches. These studies should provide important information to our longtermgoal of understanding the relationship between inflammation, lipoprotein metabolism andatherosclerosis.
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