Macrophage sphingomyelin synthase 2 deficiency decreases atherosclerosis in mice.
BACKGROUND
Sphingomyelin synthase (SMS)2 contributes to de novo sphingomyelin (SM) biosynthesis and plasma membrane SM levels. SMS2 deficiency in macrophages diminishes nuclear factor kappaB and mitogen-activated protein kinase activation induced by inflammatory stimuli.


OBJECTIVE
The effects of SMS2 deficiency on the development of atherosclerosis are investigated.


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.
Liu
Jing
J
Department of Cell Biology, State University of New York Downstate Medical Center, Brooklyn, NY 11203, USA.
Huan
Chongmin
C
Chakraborty
Mahua
M
Zhang
Hongqi
H
Lu
Da
D
Kuo
Ming-Shang
MS
Cao
Guoqing
G
Jiang
Xian-Cheng
XC
D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D002784:Cholesterol / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015850:Interleukin-6 / Q000097:blood; D017737:Macrophages, Peritoneal / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000097:blood; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D017855:Transferases (Other Substituted Phosphate Groups) / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D015850:Interleukin-6; D016328:NF-kappa B; D011973:Receptors, LDL; D014409:Tumor Necrosis Factor-alpha; D002784:Cholesterol; D017855:Transferases (Other Substituted Phosphate Groups); C070186:phosphatidylcholine-ceramide phosphocholine transferase; C543123:Sgms2 protein, mouse