The human population is routinely exposed to acrolein as high levels of acrolein have been detected in cigarette smoke, as well as in many foods and beverages that include breads, cheese, donuts, coffee, beer, wine and rum. Acrolein is also formed during the incomplete combustion of wood, plastics, gasoline and diesel fuel, as well as during the frying and re-heating of cooking oils. Indeed, a recent study by DeJarnett et al shows a significant association between acrolein exposure and cardiovascular disease risk in humans. Acrolein can also be produced endogenously as an end product of lipid peroxidation triggered by oxidative stress and as such, it is not surprising that acrolein has been detected in human atherosclerotic lesions. Studies have shown that acrolein feeding can induce endothelial activation and atherosclerosis in apoE-null mice, as well as A 286982 dyslipidemia where mice have elevated plasma cholesterol and triglyceride levels. In other studies, acro-LDL was observed in plasma of patients with atherosclerosis and was shown to contribute to the development of atherosclerosis by promoting foam cell formation in THP-1 macrophages. While acrolein appears to play a role in mediating processes that promote atherosclerosis, the mechanistic details of these pathways remain elusive. Acrolein forms adducts with cysteine, histidine, and lysine residues, and its ability to modify apoA-I has been demonstrated. Acrolein-modified apoA-I is also associated with impaired ATP-binding cassette transporter A1 -mediated cholesterol efflux in BHK cells. In this study, we move the field forward by determining the effects of acrolein modification of the entire HDL particle on cholesterol transport functions, and build on previous findings from acroleinmodification of lipid-free apoA-I alone. We have designed experiments to test our hypothesis that acro-HDL compromises HDL functions to generate a dysfunctional HDL particle that is unable to perform its athero-protective cholesterol-transport functions. There has been a growing emphasis on investigating the role of dysfunctional HDL in atherosclerosis, with evidence suggesting that modifications to HDL proteins may play a role in the pathogenesis of cardiovascular disease. Acrolein has been shown to play a role in promoting atherogenesis, but its mechanism of action has been poorly studied. Our data revealed that acrolein modification of HDL: impairs the ability of HDL to serve as an acceptor of FC from cells and reduces the efficiency of SR-BI-mediated HDL-CE selective uptake. Together, these data suggest that modification of HDL by acrolein alters the ability of HDL to fully participate in reverse cholesterol transport. To our knowledge, the AC 265347 current report is one of the only to investigate how acrolein impairs HDL function as it pertains to processes related to reverse cholesterol transport, and significantly builds on available literature that only reports the effects of acrolein modification on lipid-free apoA-I function. We verified that acrolein forms adducts with apoA-I and apoA-II and leads to protein crosslinking around the HDL particle.