Macrophages are the most prominent cell type in atherosclerotic lesions, and are associated with three hallmarks of the disease:lipid deposition, inflammation, and macrophage-derived foam cell disordered apoptosis. The ability to regulate SMS activity could become a promising approach for regulating these macrophage functions, thus influencing the atherosclerosis. SMS utilizes ceramide and phosphatidylcholine (PC) as substrates to produce sphingomyelin (SM) and diacylglycerol. SM is one of the major lipid components of cell membranes, including macrophages. SM-enriched lipid rafts in these plasma membranes provide a platform for many important cellular processes, such as cholesterol efflux and signal transduction. The SMS activity-related events listed above may well have an impact on the development of atherosclerosis. SMS has two isoforms: SMS1 and SMS2. We have evidence demonstrating that SMS activity is closely related to macrophage plasma membrane structure and function. Such findings emphasize the need for better understanding of these SMS functions in our exploration of the relationship between macrophage SMS (SMS1 and SMS2) and atherosclerosis. We now hypothesize that both SMS1 and -2 deficiencies decrease macrophage SM levels, promote cholesterol efflux, diminish the production of inflammatory cytokines and chemokines, and reduce apoptosis. They thus prevent the development of atherosclerosis, while SMS1 and -2 overproduction have the opposite effect. The major focus of this project will be to manipulate SMS activity using SMS1 and -2 gene knockout or over expression approaches to manipulate SM levels. It should be mentioned that the gene knockout mice and adenovirus-mediated expression system necessary for this work are already available in our laboratory.
Our Specific Aims are to: 1) determine the role of SMS1 and SMS2 deficiencies in macrophage cholesterol efflux, 2) explore the impact of SMS1 and -2 deficiencies and over expression on inflammatory response and apoptosis in macrophages, and 3) investigate the role of macrophage SMS1 and -2 deficiencies in atherosclerosis. Success with this proposal will help us elucidate the distinctive functions of macrophage SMS relative to atherosclerosis, determine the differences and similarities between macrophage SMS1 and macrophage SMS2 in the process of atherosclerosis, and evaluate SMS as a therapeutic target for treatment of it.

Public Health Relevance

The success of this proposal will help us to elucidate the distinctive function of macrophage SMS relative to atherosclerosis;disclose the difference and similarity between macrophage SMS1 and SMS2, in the process of atherosclerosis;and evaluate SMS as a therapeutic target for atherosclerosis treatment.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
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Liu, Lijuan
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Suny Downstate Medical Center
Anatomy/Cell Biology
Schools of Medicine
United States
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Ding, Tingbo; Kabir, Inamul; Li, Yue et al. (2015) All members in the sphingomyelin synthase gene family have ceramide phosphoethanolamine synthase activity. J Lipid Res 56:537-45
Li, Zhiqiang; Jiang, Hui; Ding, Tingbo et al. (2015) Deficiency in lysophosphatidylcholine acyltransferase 3 reduces plasma levels of lipids by reducing lipid absorption in mice. Gastroenterology 149:1519-29
Chen, Xueying; Sun, Aijun; Zou, Yunzeng et al. (2013) High PLTP activity is associated with depressed left ventricular systolic function. Atherosclerosis 228:438-42
Chakraborty, Mahua; Lou, Caixia; Huan, Chongmin et al. (2013) Myeloid cell-specific serine palmitoyltransferase subunit 2 haploinsufficiency reduces murine atherosclerosis. J Clin Invest 123:1784-97
Chakraborty, Mahua; Jiang, Xian-Cheng (2013) Sphingomyelin and its role in cellular signaling. Adv Exp Med Biol 991:1-14
Li, Zhiqiang; Ding, Tingbo; Pan, Xiaoyue et al. (2012) Lysophosphatidylcholine acyltransferase 3 knockdown-mediated liver lysophosphatidylcholine accumulation promotes very low density lipoprotein production by enhancing microsomal triglyceride transfer protein expression. J Biol Chem 287:20122-31
Subbaiah, Papasani Venkata; Jiang, Xian-Cheng; Belikova, Natalia A et al. (2012) Regulation of plasma cholesterol esterification by sphingomyelin: effect of physiological variations of plasma sphingomyelin on lecithin-cholesterol acyltransferase activity. Biochim Biophys Acta 1821:908-13
Li, Zhiqiang; Fan, Yifan; Liu, Jing et al. (2012) Impact of sphingomyelin synthase 1 deficiency on sphingolipid metabolism and atherosclerosis in mice. Arterioscler Thromb Vasc Biol 32:1577-84
Gowda, Satish; Yeang, Calvin; Wadgaonkar, Sunil et al. (2011) Sphingomyelin synthase 2 (SMS2) deficiency attenuates LPS-induced lung injury. Am J Physiol Lung Cell Mol Physiol 300:L430-40
Fan, Yifan; Shi, Fujun; Liu, Jing et al. (2010) Selective reduction in the sphingomyelin content of atherogenic lipoproteins inhibits their retention in murine aortas and the subsequent development of atherosclerosis. Arterioscler Thromb Vasc Biol 30:2114-20

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