Macrophage Sphingomyelin Synthase 2 Deficiency Decreases Atherosclerosis in Mice

Abstract

Rationale: Sphingomyelin synthase (SMS)2 contributes to de novo sphingomyelin (SM) biosynthesis and plasma membrane SM levels. SMS2 deficiency in macrophages diminishes nuclear factor B and mitogen-activated protein kinase activation induced by inflammatory stimuli. Objective: The effects of SMS2 deficiency on the development of atherosclerosis are investigated. Methods and Results: We measured cholesterol efflux from macrophages of wild-type (WT) and SMS2 knockout (KO) mice. We transplanted SMS2 KO mouse bone marrow into low-density lipoprotein (LDL) receptor (LDLr) knockout mice (SMS2 ؊/؊ 3 LDLr ؊/؊ ), creating a mouse model of SMS2 deficiency in the macrophages. We found that SMS2 deficiency caused significant induction of cholesterol efflux in vitro and in vivo. Moreover, we found that SMS2 KO mice had less interleukin-6 and tumor necrosis factor ␣ in the circulation before and after endotoxin stimulation, compared with controls. More importantly, after 3 months on a western-type diet, SMS2 ؊/؊ 3 LDLr ؊/؊ mice showed decreased atherosclerotic lesions in the aortic arch, root (57%, P<0.001), and the entire aorta (42%, P<0.01), compared with WT3 LDLr ؊/؊ mice. Analysis of plaque morphology revealed that SMS2 ؊/؊ 3 LDLr ؊/؊ mice had significantly less necrotic core area (71%, P<0.001), less macrophage content (37%, P<0.01), and more collagen content (35%, P<0.05) in atherosclerotic lesions. We also found that SMS2 ؊/؊ 3 LDLr ؊/؊ mice had significantly lower free cholesterol and cholesteryl ester levels in the brachiocephalic artery than WT3 LDLr Key Words: macrophage sphingomyelin synthase deficiency Ⅲ sphingomyelin biosynthesis Ⅲ cholesterol efflux Ⅲ inflammation Ⅲ atherosclerosis F oam cell formation caused by excessive accumulation of cholesterol in the macrophages is a pathological hallmark of atherosclerosis, 1 which is also known to be an inflammatory disease. 2 The accumulation of macrophage-derived foam cells in the vessel wall is always accompanied by the production of a wide range of chemokines and cytokines that regulate the turnover and differentiation of immigrating and resident cells and subsequent plaque development. 2 Thus, promoting cholesterol efflux from cholesterol-laden macrophages, as well as diminishing their inflammatory response, can both be significant antiatherogenic approaches.The interaction between sphingomyelin (SM), cholesterol, and glycosphingolipid drives the formation of plasma membrane rafts, 3 and in some cells, caveolae. 4,5 SM is synthesized by sphingomyelin synthase (SMS), which transfers the phosphorylcholine moiety from phosphatidylcholine (PC) onto ceramide. 6 Two SMS genes, SMS1 and SMS2, have been cloned, and their subcellular localization characterized. 7,8 SMS1 is found in the trans-Golgi apparatus, whereas SMS2 is predominantly located in the plasma membranes. 7,9 Our laboratory and others have shown that SMS1 and SMS2 expression levels correlate positively with those of SM in the lipid rafts. 10 -12 Furthermore, SMS1 has been implicated in the regulation of lipi...

Erratum

“…Mammals contain two SMS isoforms, namely SMS1, primarily responsible for de novo SM synthesis in the lumen of the trans Golgi, and SMS2, presumably serving a role in regenerating SM from ceramides liberated by SMases on the cell surface (12)(13)(14)(15). Studies in mice revealed a role of SMS1 and SMS2 in inflammation, atherosclerosis, and dia betes (15)(16)(17), suggesting that these enzymes represent rel evant pharmacological targets. Besides bulk amounts of SM, mammals also produce small quantities of ceramide phos phoethanolamine (CPE), a widespread but poorly studied SM analog.…”

Chitosan Oligosaccharides Attenuate Atherosclerosis and Decrease Non-HDL in ApoE-/- Mice

“…5F), whereas no change was observed in the expression of the other genes. We previously reported that the COS treatment may promote the expression of LXR in the liver 14) . In the present study, we additionally found that the LXR expression was significantly enhanced with the treatment of COS (Fig.…”

“…The aortas were dissected and the arches were exposed for photographing 14) . A quantitative analysis of an aortic lesion en face assay was performed as previously described 14,15) .…”

“…A quantitative analysis of an aortic lesion en face assay was performed as previously described 14,15) . The plaque morphological histomorphometric characters were analyzed via oil red O staining, Masson's staining, or hematoxylin/eosin (H&E) staining.…”

Diet-induced lipid accumulation in phospholipid transfer protein-deficient mice: its atherogenicity and potential mechanism

“…Atherosclerosis was determined as previously described ( 19 ). Briefl y, Pltp KO/ Apoe KO and Apoe KO mice were fed the high-fat diet for 7 weeks.…”