Selective reduction in the sphingomyelin content of atherogenic lipoproteins inhibits their retention in murine aortas and the subsequent development of atherosclerosis.
OBJECTIVE
We used the sphingomyelin (SM) synthase 2 (Sms2) gene knockout (KO) approach to test our hypothesis that selectively decreasing plasma lipoprotein SM can play an important role in preventing atherosclerosis.


RESULTS
The sphingolipid de novo synthesis pathway is considered a promising target for pharmacological intervention in atherosclerosis. However, its potential is hampered because the substance's atherogenic mechanism is not completely understood. We prepared Sms2 and apolipoprotein E (Apoe) double-KO mice. They showed a significant decrease in plasma lipoprotein SM levels (35%, P<0.01) and a significant increase in ceramide and dihydroceramide levels (87.5% and 27%, respectively; P<0.01) but no significant changes in other tested sphingolipids, cholesterol, and triglyceride. Non-high-density lipoproteins from the double-KO mice showed a reduction of SM, but not cholesterol, and displayed less tendency toward aortic sphingomyelinase-mediated lipoprotein aggregation in vitro and retention in aortas in vivo when compared with controls. More important, at the age of 19 weeks, Sms2 KO/Apoe KO mice showed a significant reduction in atherosclerotic lesions of the aortic arch and root (52%, P<0.01) compared with controls. The Sms2 KO/Apoe KO brachiocephalic artery contained significantly less SM, ceramide, free cholesterol, and cholesteryl ester (35%, 32%, 58%, and 60%, respectively; P<0.01) than that of the Apoe KO brachiocephalic artery.


CONCLUSIONS
Decreasing plasma SM levels through decreasing SMS2 activity could become a promising treatment for atherosclerosis.
Fan
Yifan
Y
Department of Cardiology, Renmin Hospotal, Wuhan University, Wuhan, China.
Shi
Fujun
F
Liu
Jing
J
Dong
Jibin
J
Bui
Hai H
HH
Peake
David A
DA
Kuo
Ming-Shang
MS
Cao
Guoqing
G
Jiang
Xian-Cheng
XC
D000818:Animals; D001011:Aorta / Q000378:metabolism* / Q000503:physiopathology; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D008074:Lipoproteins / Q000378:metabolism*; D051379:Mice; D013109:Sphingomyelins / Q000378:metabolism*; D017855:Transferases (Other Substituted Phosphate Groups) / Q000235:genetics*
D008074:Lipoproteins; D013109:Sphingomyelins; D017855:Transferases (Other Substituted Phosphate Groups); C543123:Sgms2 protein, mouse
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