Summary Atherosclerosis contributes significantly to cardiac related morbidity and mortality in the aging population of veterans. Plasma low density lipoprotein (LDL) and its precursor very low density lipoprotein (VLDL) are two atherogenic lipoproteins. LDL initiates atherosclerosis through its retention in the subendothelial space of arterial walls. Statin-mediated LDL lowering is now the mainstay of cardiovascular disease treatment. However, despite the efficacy, there are many instances of unresponsiveness and intolerance. There is thus an urgent need for additional approaches for lowering plasma LDL, preferably acting synergistically with statins. Blocking liver VLDL secretion and promoting LDL clearance have long been recognized as an effective LDL lowering strategies. Those are different from the use of statins. It is known for a long time that plasma phosphatidylethanolamine (PE) level is a better predictor for human atherosclerosis. However, how to regulate PE and what is the mechanism linking PE with atherosclerosis are not quite understood. PE is one of the important lipid components on VLDL and LDL, and its level influences the development of atherogenesis in animal models. Thus, study PE regulation may provide an important clue for lowering VLDL and LDL, and for a new treatment of human atherosclerosis. Sphingomyelin synthase (SMS) gene family has three members: SMS1 and SMS2 have SM synthase activity, while SMS-related protein (SMSr) has no SM synthase activity but has ceramide phosphorylethanolamine (CPE) synthase activity in test tubes. Although SMSr is ubiquitously expressed in all tested tissues, the CPE levels in most of mammalian tissues or cells are undetectable under chow or high fat/cholesterol diets. Therefore, SMSr is not a functional CPE synthase in vivo and its real biological function need to be elucidated. From the CPE synthase reaction, we notice that SMSr should have a potential PE-PLC activity, i.e. hydrolyzing PE into diacylglycerol and phosphorylethanolamine, which could be involved in tissue PE steady state regulation. Based on preliminary results of this study, we then hypothesize that SMSr is a functional PE-PLC in vivo. Given the fact that PE levels are involved in VLDL production, LDL clearance, and the development of atherosclerosis, SMSr/PE-PLC should be a novel and promising target for lowering LDL. We have three specific aims: 1. Investigate whether SMSr is a functional PE-PLC. 2. Evaluate the effects of blocking SMSr/PE-PLC on VLDL production and LDL clearance. 3. Examine the role of SMSr/PE-PLC deficiency in the development of atherosclerosis. Insights gained from the proposed studies will allow us to evaluate SMSr/PE-PLC as a target for preventing and treating human atherosclerosis.