: Macrophages (MPhi) and endothelial cells in atherosclerotic lesions express two enzymes arising from the acid sphingomyelinase (SMase) gene: secretory (S) and lysosomal (L-) SMase. S-SMase promotes lipoprotein aggregation, which leads to subendothelial lipoprotein retention and MPhi foam cell formation. New data,however, suggest that lysosomal (L-) SMase facilitates cholesterol efflux. Thus, we hypothesize that while S-SMase promotes foam cell lesions, L-SMase plays a role in foam cell regression. Moreover, acid Smase deficient MPhis are protected from free cholesterol-induced MPhi apoptosis, suggesting a role for S- or L-SMase in lesional MPhi death. Our overall objective is to explore these hypotheses and other roles of S- and L-SMase in atherogenesis using genetically engineered mouse models and cultured MPhis.
In Aim 1, acid SMase knockout mice will be used to define further the net effect of S- and L-SMase deficiency on foam cell lesions and on aortic LDL retention, degradation, and aggregation in vivo. In addition, we will create two new mouse models specifically to define the roles of S- vs. L-SMase in atherogenesis.
In Aim II, we will address three areas in which S- and L-SMase may influence Mo biology related to atherogenesis: (1) cDNA microarrays will be used to test the hypothesis that MPhi interaction with matrix-retained and S-SMase-aggregated LDL alters gene expression; (2) the mechanisms and consequences of SMase-mediated death will be investigated in cultured MPhis and in vivo; and (3) in collaboration with Project 6, we will explore the mechanisms of defective cholesterol efflux in SMase-deficient MPhis.
In Aim 1, through a large multiethnic study, we will explore our finding that high plasma sphingomyelin is a potent and independent risk factor for coronary artery disease in humans. To investigate a possible mechanism of this association, we will test the hypothesis that human remnant lipoproteins are relatively rich in sphingomyelin, rendering them susceptible to S-SMase and converting them into potent inducers of foam cells following S-SMase treatment. This work is intimately related to the overall theme of the SCOR-the investigation of arterial-wall molecules involved in atherogenesis using genetically manipulated mouse and cell-culture models-and will involve collaborations with Projects 6, 7, and 8 and use of the Gene Expression, Clinical, and Pathology Cores.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Columbia University (N.Y.)
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Chen, Han; Cade, Brian E; Gleason, Kevin J et al. (2018) Multiethnic Meta-Analysis Identifies RAI1 as a Possible Obstructive Sleep Apnea-related Quantitative Trait Locus in Men. Am J Respir Cell Mol Biol 58:391-401
Johnson, Dayna A; Hirsch, Jana A; Moore, Kari A et al. (2018) Associations Between the Built Environment and Objective Measures of Sleep: The Multi-Ethnic Study of Atherosclerosis. Am J Epidemiol 187:941-950
Johnson, Dayna A; Lane, Jacqueline; Wang, Rui et al. (2017) Greater Cognitive Deficits with Sleep-disordered Breathing among Individuals with Genetic Susceptibility to Alzheimer Disease. The Multi-Ethnic Study of Atherosclerosis. Ann Am Thorac Soc 14:1697-1705
Cade, Brian E; Chen, Han; Stilp, Adrienne M et al. (2016) Genetic Associations with Obstructive Sleep Apnea Traits in Hispanic/Latino Americans. Am J Respir Crit Care Med 194:886-897
Mayurasakorn, Korapat; Williams, Jill J; Ten, Vadim S et al. (2011) Docosahexaenoic acid: brain accretion and roles in neuroprotection after brain hypoxia and ischemia. Curr Opin Clin Nutr Metab Care 14:158-67
Devlin, Cecilia M; Leventhal, Andrew R; Kuriakose, George et al. (2008) Acid sphingomyelinase promotes lipoprotein retention within early atheromata and accelerates lesion progression. Arterioscler Thromb Vasc Biol 28:1723-30
Pan, Meihui; Maitin, Vatsala; Parathath, Sajesh et al. (2008) Presecretory oxidation, aggregation, and autophagic destruction of apoprotein-B: a pathway for late-stage quality control. Proc Natl Acad Sci U S A 105:5862-7
Williams, Kevin Jon; Feig, Jonathan E; Fisher, Edward A (2008) Rapid regression of atherosclerosis: insights from the clinical and experimental literature. Nat Clin Pract Cardiovasc Med 5:91-102
Tabas, Ira; Williams, Kevin Jon; Boren, Jan (2007) Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation 116:1832-44
Williams, Kevin Jon; Qiu, Gang; Usui, Hitomi Katoaka et al. (2007) Decorin deficiency enhances progressive nephropathy in diabetic mice. Am J Pathol 171:1441-50

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