Macrophage Sphingomyelin Synthase 2 Deficiency Decreases Atherosclerosis in Mice

Rationale: Sphingomyelin synthase (SMS) 2 contributes to de novo sphingomyelin (SM) biosynthesis and plasma membrane SM levels. SMS2 deficiency in macrophages diminishes nuclear factor kappa 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(-/-)-> 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 alpha in the circulation before and after endotoxin stimulation, compared with controls. More importantly, after 3 months on a western-type diet, SMS2(-/-)-> 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 WT -> LDLr-/- mice. Analysis of plaque morphology revealed that SMS2(-/-)-> 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(-/-)-> LDLr-/- mice had significantly lower free cholesterol and cholesteryl ester levels in the brachiocephalic artery than WT -> LDLr-/- mice (33 and 52%, P<0.01 and P<0.001, respectively). Conclusions: SMS2 deficiency in the macrophages reduces atherosclerosis in mice. Macrophage SMS2 is thus a potential therapeutic target for treatment of this disease. (Circ Res. 2009; 105: 295-303.)